CZ2003733A3 - Process for preparing chiral compounds - Google Patents

Abstract

The invention relates to a method for producing chiral compounds according to the condition of a 1.4 Michael reaction in addition to a compound of general formula (31) and the use thereof as an antalgic.

Description

The invention relates to a process for the preparation of chiral compounds under 1,4-Michael addition conditions and corresponding compounds.

BACKGROUND OF THE INVENTION

Asymmetric synthesis

The central theme of this application is asymmetric synthesis. The carbon atom can form four bonds which are spatially arranged tetrahedrally. If the carbon atom carries four different substituents, two arrangements are possible that behave as an object and its image in a mirror. These compounds are called enantiomers. The chiral (derived from the Greek cheir = hand) molecule has no mirror rotation axis. They distinguish only by their physical properties, that is, the direction in which they rotate linearly polarized light to the same degree. In an achiral environment, both enantiomers have the same chemical, biological, and physical properties. In contrast, in a chiral environment, such as in the human body, their properties can vary widely.

(S) ^H2N X ^X OH oh ₂ n bitter taste

HO '- ^NH2 nh ₂ for a sweeter taste

Asparagus in (S) ch ₃

ch ₂ aromas of lemons

Limonen

fragrance of oranges

Figure 1: Examples of enantiomers with different biological properties

The interaction of enantiomers is always different with receptors and enzymes, so different physiological effects may occur in nature (see Figure 1) [1]. For example, the (S) form of asparagine (S from Latin sinister = left) has a bitter taste, while the (R) form (R from Latin rectus = right) tastes sweet. A common example is limonene, which occurs in citrus fruits. The (S) -form resembles the smell of lemons, while the (R) -form smells orange. In general, the descriptive text refers to references in Arabic numbers in square brackets, which refer to the lists below and to the list of references preceding the claims. If a 1 iterature source is followed by a Roman number after the majority quoted name of the first author, it means the corresponding value (in Arabic numbers), as well as in cases where the value is not in square brackets.

The preparation of enantiomers can be carried out in three different ways:

classical racemate resolution

· · «

- use of chiral building elements from nature (chiral pool)

- asymmetric synthesis

Especially asymmetric synthesis has gained great importance. These include enzymatic, stoichiometric and also catalytic methods. Asymmetric catalysis is by far the most ineffective external method since maximum of the optically active substance can be produced with the minimein chiral catalyst.

The discoveries of Pasteur [2], LeBel [3] and van ΐ Hoff [4] have increased interest in optically active substances because of their recognition for the complex chemistry of life.

D.Enders and V.Hoffmann [1] define asymmetric synthesis as follows:

Asymmetric synthesis is a reaction in which the chiral moiety is made chiral so that the stereoisomeric products (enantiomers or diastereomers) are formed in unequal amounts.

about chi rali you.

ρ ret: r.iwov \ cl

In order to successfully achieve asymmetric synthesis, diastereomorphic transition states must occur with different energy during the reaction. These determine which enantiomer is produced in excess. Diastereomorphic transition states with different energies can be produced by additional information

These can be delivered chiral to form diastereomorphic. Solvent!

modified reagents or chiral catalysts.

An example of an asymmetric catalyst is represented by Sharpless epoxidation [5 j. Here, from Lewis acid Ti (O-i-Pr) 4 a

4 4 ·· »·

4 · 4 »44

4 4 4 4 4

444 4,444 4 4

The (-) - diethyl tartrate forms the chiral catalyst shown in Figure 2.

Figure 2: Sharpless Chiral Catalyst Catalyst [5]

With the aid of this catalyst, allyl alcohols 1 can be epoxidized with a high enanthonic selectivity to 2 (see Figure 3) using tert-butyl hydroperoxide as the oxidizing agent.

In general, the descriptive text uses predominantly, but not always, the corresponding bold and underlined numbers to designate and characterize compounds, especially those shown in the figure or indicated as a general formula.

TKO-i-Prk (CHCOOHDCM

Figure 3: Sbarpless epoxidation

The Sharpless reaction is a widespread reaction, especially in the chemistry of natural substances. By nucleophilic ring opening, compounds such as alcohols, ethers or vicinal alcohols with an optical purity of more than 90% can be easily formed.

Michael's reaction

The Michael reaction is of great importance in organic synthesis and is one of the most important reactions to form a C-C junction. It has enormous synthesis potential.

Since there are a number of different Michael additions, some examples will be given in the next chapter.

The emphasis will be placed on Michael additions with thiols by asymmetric catalysis.

Classical Michael addition

The classical Michael reaction [6], as shown in Figure 4, is carried out in a protic solvent. In this process, the carbonyl compound 3 is first deprotonated in the α-position of the base to form the enolate 4.

R ¹ , R ² , R ³ = H, Alkyl, Aryl R ⁴ = H, Alkyl, Alkoxy. Aryl

Figure 4: Classic Michael addition «« »• 4

This enolate anion 4 (Michael donor) binds 1,4-addition to the α, β-unsaturated carbonyl compound 5 (Michael acceptor). After reprotonization, Michael adduct 6, which is 1,5-diketone, is then formed.

The most important side reaction that may occur is the aldoi reaction [5]. The aldol reaction is a kinetically preferred process, but this 1,2-addition is reversible. Since the Michael addition is irreversible, a thermodynamically more stable 1,4-adduct is obtained at higher temperatures.

General Michael addition

There are currently many related 1,4-additions in which the Michael acceptor and / or donor differ from the classical Michael addition. They are often called Michael's or summarized under the superior term of Michael's addition. The general Michael addition is now referred to as all 1,4-nucleophile donors (Michael donor) to the C-C multiple bond (Michael acceptor) activated by electron withdrawing groups. In doing so, the nucleophile 1,4-adds to the activated C-C 7 multiple bond to form adduct 8 (see Figure 5) [7],

0 0 · 0

EVG = electron attracting group

N'u ⁺ = carbanion, nucleophile S-, Se-, Si-, Sn-, O- or NE ⁺ = H, alkyl and the like.

Figure 5: General Michael reaction

When working in an aprotic solvent, the intermediate carbanion formed can react with electrophiles to form 9 (E = H). If the electrophile is a proton, it is a normal Michael addition. If, on the other hand, it is a carbon electrophile, it is said that the Michael reaction is tandem because, after the 1,4-addition, the electrophile is added as a second step [8],

In addition to α, β-unsaturated carbonyl compounds, vinylog sulfones [9], sulfoxides [10], phosphonates [11] and nitroolefins [12] can be used as Michael acceptors.

Not only enolates but also other carbanions, as well as other hetero-nucleophiles such as nitrogen [3], oxygen [14], silicon [15], tin [16], selenium [17] and sulfur [18] serve as nucleophiles.

One way to introduce asymmetric induction into Michael's addition of thiols to Michael's acceptors is intra-ecular control. Prior to the reaction either in the Michael acceptor or in the thiol there is a stereogenic center which controls the stereochemistry of the Michael reaction.

Using the pure enantiomer of pyrrolidinone, N-acrvic acids were similar to Evans with oxazolidinone.

K. Tomioka et al. [19] induced Michael addition with thiols to 2-alkyl acrylic acids, as shown in Figure 6:

1-2 Áq Mg (ClO ₄ );

CH ₃ CH ₂ CN -70 ° C

R = Me, i-Pr, Bu, Phe = 86-98%

Figure 6

Asymmetric addition of thhiophenol to pyrrolidinone N-acrylic acid 10

The reaction was previously controlled by (E / Z) -geometry of acrylicpyrrolidinone. Asymmetric induction is carried out by the (R) -triphenylmethoxymethyl group at the 5-position of the pyrrolidinone. This space filling tab covers the half Re-side of the double bond during the reaction so that only the opposite Si-side is attacked. With a single addition of 0.8 equivalents of thiolate or Mg (CO ₄ ) 2, even up to 98% could be achieved. The de-value is understood to mean the proportion of the pure enantiomer of the product, the other residue which is absent to 100% is a racemic mixture. The ee value is also defined dentically,

There are many examples of the construction of a new stereogenic center, but Michael's addition of intramolecular control thiols, in which two stereogenic centers are formed in one step, occur sparsely.

Used for Michael addition, at the center, the oxazolidinones according to Evans about chirality to Michael's accepto.Naito et al. [20] created two new ones [21] to introduce ru information (Figure 7):

(E) -12, (2) -12

13c: ‘-SPh (3 ·, ^ 13d: —SPh (3'S))

13a: ..... 'SPh (3'R)

13b: SPh (3'S)

Figure 7: Michael addition to form two stereogenic centers

Table 1: Experimental conditions and ratios of both newly created centers

EDUKT Yield [%] Temperature [° C] dr [%] 13 and 13 b 13 c 13 d (E) -12 84 RT > 55 <1 <1 > 43 (E) -12 98 - 50 > 89 <1 4 6 1E) -12 96 - 50 > 87 <1 4 8 (E) - 1 2 95 -30-- 10 3 4 <1 > 92

To achieve high excesses of diastereomers (80-86%) and enantiomers (98%), it is added to 1 equivalent

0 «* 0« 0

0 0 * «

chiral imide 12 is a solution of 10 equivalents of thiophenol and 0.1 equivalents of lithium thiophenolate in THF at low temperatures (-50 - -10 ° C). When the methyl group of 12 in the 3-position is exchanged for a phenyl group, a diastereomeric excess of > 80% is still achieved in the same reaction. However, the enantiomeric excesses are only between 0 and 50%. Stereocentre in position 2 could be selectively controlled in this case, while the center in position 3 achieved only slight selectivity.

Michael's addition of kata Skied by chiral bases,

Michael's addition of thiols to α, β - unsaturated carbonyl compounds under catalysis with bases such as triethylamine or piperidine has been known for some time [22].

T. Mukaiyama and et al. [23] investigated the use of hydroxyproline 14 derivatives as a chiral catalyst:

Table 2: Chiral base of hydroxyproline

I4a-e

Number R1 R2 14a H Phenyl 14b H Cyclohexyl 14c H 1,5-dimethylphenyl 14d H 1 - diesel L 14e Me Phenyl

The addition of thiophenol (0.8 equivalents) and cyclohexanone (1 equivalents) with hydroxypro-14-a-e derivatives (0.008 equivalents) in toluene was investigated. As a result, an ee of 72% can be achieved using 14d.

Many alkaloids have also been tested for chiral basic catalysis. Cinchona alkaloids [24], [25] and ephedrine alkaloids have been used particularly frequently.

Thus H.Vynberg [26] and Michael addition control of lohexanones with Ci alkaloids (see Figure 8):

tested in detail the catalysis of thiophenols for α, β-unsaturated cyclone and ephedrine alkaloids

+

PhSH

Cinchona Alkaloids Ephedrine alkaloids

Figure 8: Michael's reaction driven by Cinchona alkaloids and ephedrine ulkaloids

Table 3: Excess enantiomers using different alkaloids in Michael addition

C. J currency Rl R2 R3 R4 ee [%] 15a Chin i n C2H3 OH H 0CH3 44 15b Cinchon i din C2H3 OH H H 62 15c Dihyd roquinine C2H5 OH H 0CH3 35 15d Epichin i n C2H3 H OH OCH3 18 15e Acetylein C2H3 OAc H 0CH3 7 15f Deoxycinchonid in C2H3 H H H 4 15g Epichhlorci nchonidin C2H3 H Cl H 3 16a (-) - N-methylephedrin OH - - - 29 16b N, N-dimethylamphetamines n H - - - 0

As can be seen from Table 3, a slight change in the residue R1 - R4 in alkaloids 15 and 16 results in a marked change in the excess of the enantiomers. This means that the catalyst must adapt to the starting materials. If, for example, N-methylthiophenol is used instead of thiophenol, a significant deterioration of the enantiomeric excess has been recognized for the same catalysts,

Michael addition catalyzed by chiral. Lewis acids i

Simple catalysis of Michael addition of thiols to Michael receptors by simple Lewis acids such as, for example, titanium tetrachloride has been known for some time with good yields [27],

For catalysis with chiral Lewis acids, there are several examples in which oxazolidinones of N-acrylic acid are used as in the case of intramolecular control (Chapter 1.2.3). However, these do not contain any chiral center. Additional carbonyl groups of the introduced oxazolidinone ring are needed to chelate the metal atom of the Lewis acid-17 chiral. Lewis acid 18 was used by D.A.Evans to add silylenol ethers to oxazolidinone N-acrylic acid 17 and Lewis acid 18 complex with diastereomeric excesses of 80-98% and enantiomeric excesses of 75-99% (see Figure 9) [28].

Figure 9: Lewis acids chiral 18 and 19 that bind to oxazolidinone N-acrylic acid 17

Lewis acid Ni - (R, R) - DBFOX / Ph (DBFOX / Ph =

4,6-dibenzofuranediyl-2,2-bis- (4-phenyloxazoline) 19 was used by S. Kanemasa to add thiols to 17 [29]. It achieved enantiomeric excesses up to 97% with good yields.

Accordingly, 1,1-binaphthols (Binol) were also bound to metal ions to form a chiral Lewis acid (see Figure 10). Thus he synthesized B.L. Fering [30] LiAl binolo complex 20, which he used in Michael addition of α-nitroesters to α, β-unsaturated ketones. At -20 ° C in THF, using 10 mol. % LiAlBinol 20 Michael adduct with up to 71% ee.

Shibasaki [31] uses NaSmBinol complex 21 in Michael addition of thiols to α, β-unsaturated acyclic ketones At -40 ° C Michael obtained adducts with enantiomeric excesses of 75 to 93%.

from ° -l ⁰ A '

4a

AlLiBinol

SmNaBinol

Figure 10 (R, R) -Binaphthol complex of aluminum and samarium

These Michael states, whereby the chiral Lewis acids form di-astereomorphic in the donor and acceptor, control of the reaction is achieved.

Transition delivery

Control of Michael addition by complexation of thiated nucleophile Lu

Another type of nucleophile (Michael donor) intervention in the reaction to control it is the complexation of the lithiated donor with an external chiral ligand.

· *** * · »9 · · β * ···

Tomioka et al [32] to this end, they tested many external chiral ligands for the controlled intervention of organometals in various reactions, such as aldol addition, alkylation of enolates, Michael addition, and so on. Figure 11 shows some examples of the enantiomerically pure compounds with which Tomioka complexed the organometals.

Figure 11: Examples of pure enantiomeric ligands to control organolithium intervention

Thus, by way of example, with diethyl ether 22, he controlled the aldol aid of dimethylmagnesia to benzaldehyde and obtained an enantiomeric excess of 22%. In contrast, with lithium amide 23, when the BuLi was added to the benzaldehyde, the enantiomer excess was 90%. When the diethysin was added to the benzaldehyde, the enantiomer excess was 24% with 90%. With the proline derivative 26, it controlled the addition of organometals to Michael systems with an enantiomeric excess of up to 90%.

With 27, only 50% could be achieved in alkylation of cyclic enamines.

Later, Tomioka extended his synthesis by using not only organolithium compounds, but also 1 ithiumthilates [33]. In doing so, he used chiral dimethylether as an exemplary 25. sparteine or a chiral diether. It is related to 27 and has another chirality center due to the phenyl substituents at position 2. When Michael's addition of lithium thiolates to methyl acrylate, an enantiomeric excess of 90%, but only 6%, was obtained for this chiral diether.

Considering that in all cases the chiral compound is only used in a catalytic amount of 5 to 10 mol%, the excess of the enantiomer is in part very favorable.

The torsion eyes postulated the concept of an asymmetric oxygen atom for dimethylether 28 in non-polar solvents [34]:

Figure 12: Chiral chelate model of organolithium compounds n

As shown in Figure 12, residues 28 in complex 29 are in the all-trans position due to steric effects.

Asymmetric carbon atoms in the ethylene bridge make adjacent oxygen atoms asymmetric centers. According to X-ray structure analysis, these oxygen atoms, which chelate lithium, at 2.9 are tetrahedral.

·· · ♦ coordinated. Therefore, the chirality information is given in the direct vicinity of the chelated lithium atom by the space-intensive residue R2.

SUMMARY OF THE INVENTION

SUMMARY OF THE INVENTION It was therefore an object of the present invention to generally develop an asymmetric synthesis under Michael addition conditions which overcomes the disadvantages of the prior art and provides good yields.

In particular, a simple synthesis route should be found to produce the 2-formylamino-3-dialkylalkylacrylic acid ester 30 and to separate the (E, Z) -mixed acrylic ester mixtures 30. Also, a pathway to Michael addition with thiols starting from from synthesized Michael acceptor 30. For this addition, a Lewis acid catalyst should first be found, which may later be provided with chiral ligands to drive (see Figure 13). Excess diastereomers and enantiomers of Michael adducts 31 would be directly determined.

+ R ^J 5H___

Michael addition catalyst =? control of catalysis

Figure 13: Task in the Invention

Therefore, the main object of the invention is a process for the preparation of a compound of formula 9

EWG wherein the compound of formula (7) is reacted by 1,4-Michael addition with nucllecfil of the following scheme under suitable Nu 'according to

where residues

A. D and G are the same or different independently of each other • 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9 and are any substituents,

E is selected from H or aqvLu,

Nu is selected from nucleophiles C-, S-, Se-, Si-, O- or N- ?.

EVG is an electron-attracting group, characterized in that the conditions are selected such that stereoisomeric, especially enantiomeric and / or diastereomeric products are produced in unequal amounts. In this connection, it is particularly advantageous if the nucleophile Nu 'is the nucleophile S-.

A further object of the invention is a process for the preparation of a compound of formula 31

where

R 1, R 2 and R 3 are independently selected from alkyl of 1 to 10 carbon atoms, saturated or unsaturated, mono- or polysubstituted or unsubstituted; and * indicates a stereoselective center

R 4 is selected from alkyl of 1 to 10 carbon atoms, saturated or unsaturated, branched or branched, singly or multiply substituted or unsubstituted;

• φ ♦ φ φ φ φ · · * * φ φ φ · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

C 3 to C 8 cycloalkyl, saturated or unsaturated, mono- or multiply substituted or unsubstituted; or aryl, C 3 -C 8 cycloalkyl or heteroaryl bonded via saturated or unsaturated C 1 -C 3 alkyl, in each case unsubstituted or mono- or multiply substituted;

wherein the compound of formula 30 is reacted under Michael addition conditions with a compound of formula R 2 SH according to the following reaction scheme:

O

wherein the compounds of the formula R @ 5 SH are used as 1-lithium thiolates or in the reaction or prior to the T reaction react to lithium thiolates and / or chiral catalysts selected from: auxiliary chiral reagents, in particular diether (S, S) - 1,2-dimethoxy- 1,2-diphenyl ethane; Lewis acids and / or Bronsted bases or combinations thereof are used and optionally subsequently hydrolyzed with bases, in particular sodium hydroxide, and optionally purified, preferably by column chromatography.

* 4 t I • 4 * · · <

* ♦ · · · · · · · · · · ·

For the purposes of the present invention, alkyl and cycloalkyl radicals are saturated and unsaturated, but not aromatic, branched, unbranched and cyclic hydrocarbons, which may be unsubstituted or mono- or polysubstituted. The alkyl group having 1 to 3 carbon atoms is an alkyl group having 1, 2 or 3 carbon atoms, an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1, 2, 3 or 4 carbon atoms, an alkyl group having 1 to 5 carbon atoms alkyl groups having 1, 2, 3, 4 or 5 carbon atoms, alkyl group having 1 to 6 carbon atoms alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, alkyl group having 1 to 7 carbon atoms alkyl 1, 2, 3, 4, 5, 6 or 7 carbon atoms, alkyl of 1 to 8 carbon atoms alkyl group with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkyl group of 1 up to 10 carbon atoms an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and an alkyl group having 1 to 18 carbon atoms an alkyl group having 1, 2, 3, 4, 5, 6 7 8 9 10 11 12

13, 14, 15, 16, 17 or 18 carbon atoms. Further, C 3 -C 4 cycloalkyl is C 3 or C 4 cycloalkyl, C 3 -C 5 cycloalkyl is C 3, C 4 or C 5 cycloalkyl, C 3 -C 6 cycloalkyl is C 3 cycloalkyl. , 4, 5 or 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl of 3, 4, 5, 6 or 7 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3, 4, 5, 6 7 or 8 carbon atoms, a 4 to 5 carbon cycloalkyl group having 4 or 5 carbon atoms, a 4 to 6 carbon cycloalkyl group having 4, 5 or 6 carbon atoms,

F ··· ·· • ·

9 · · · · F · 1 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

II FF Cycloalkyl of 4 to 7 carbon atoms Cycloalkyl of 4, 5, 6 or 7 carbon atoms, cycloalkyl group of 5 to 6 carbon atoms cycloalkyl having 5 or 6 carbon atoms and cycloalkyl having 5 to 7 carbon atoms cycloalkyl having 5, 6 or 7 carbon atoms. In relation to a cycloalkyl group, the term also includes saturated cycloalkyls in which one or two carbon atoms are replaced by a heteroatom selected from the group consisting of sulfur, nitrogen and oxygen. The term cycloalkyl also includes, in particular, one or more, preferably once unsaturated, cycloalkyls without a heteroatom in the ring, unless the cycloalkyl is an aromatic system. Preferably, the alkyl or cycloalkyl radicals are methyl, ethyl, vinyl (ethenyl), propyl, allyl (2-propenyl), 1-propynyl, methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-propyl. , 1-dimethylpropyl, 1,2-dimethylpropyl,

2,2-dimethylpropyl, hexyl, 1-methylpentyl, cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl. cycloheptyl and cyclooctyl, but also adamantyl, difluoromethyl, trifluoromethyl or hydroxymethyl, as well as pyrazolinone, oxopyrazolinone, [1,4] dioxane or dioxolane.

In this context, in the context of an alkyl and cycloalkyl group, unless expressly defined otherwise, the term sub-substituted within the meaning of the present invention means substitution by at least one or optionally more hydrogen, fluorine, chlorine, bromine and iodine atoms, amino, SH or hydroxyl groups with us being multiple substituted or optionally substituted

4 • 4

4 4 *

In the case of multiple substitution is meant that the substitution is carried out both on different and on the same atoms multiple times on the same or different substituents, for example three times on the same carbon atoms as in the case of the trifluoromethyl group , or at various locations such as -CH (OH) -CH = CH-CHCl ₇ . Particularly preferred substituents here are fluorine and chlorine atoms and hydroxy. In the case of cycloalkyl groups, the hydrogen atom may also be replaced by an O-alkyl group having 1 to 3 carbon atoms or an alkyl group having 1 to 3 carbon atoms (in each case mono- or polysubstituted or unsubstituted), in particular methyl, ethyl, n-propyl , i-propyl, trifluoromethyl, methoxy or ethoxy.

The term (CH ₂ ) ₂ -g ^means - groups -CH ₇ -CH ₂ -CH ₇ -,

-ch ₂ -ch ₂ -ch ₂ -ch ₂ -, -ch ₂ -ch ₉ -ch _? -ch ₂ -ch ₇ and -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₇ -CH ₂ -, the term (CH ₂ ) ₄ - refers to the groups -CH ₂ -, -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ - and -CH ₂ -CH ₂ -CH ₂ -CH ₂ and (- (^ 2) 4.5 means -CH ₂ -CH ₂ -CH ₂ -CH ₂ and -CH ₂ -CH ₂ -CH ₂ -CH ₇ -CH ₂ - and the like.

The term "aryl radical" or "aryl" refers to ring systems with at least one aromatic ring but without heteroatoms in also only one of the rings. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, in particular 9H-fluorenyl or anthracenyl, which may be unsubstituted or mono- or polysubstituted.

The term heteroaryl or heteroaryl radical refers to heterocyclic ring systems with at least one unsaturated ring containing one or more heteroatoms from the group consisting of nitrogen, oxygen and / or sulfur and also may be mono- or polysubstituted . For example, they may be selected from the group consisting of heteroaryls furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, benzo [1,2,5] thiadiazole, benzothiazole, indole, benzotriazole, benzodioxolane, carbazole, indole and quinazoline.

In this context, in the context of an aryl and heteroaryl group, a substituted aryl substitution or a heteroaryl group represented by R and OR, a halogen atom, preferably a fluorine and / or chlorine atom, a trifluoromethyl group, a cyano group, a nitro group, a NR4R25 group, C 1 -C 6 (saturated), C 1 -C 6 -alkoxy, C 3 -C 8 -cycloalkoxy, C 3 -C 8 -cycloalkyl or C 2 -C 6 -alkylene.

3

In this case, R represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, preferably an alkyl group having 1 to 6 carbon atoms, an aryl group or a heteroaryl group, or, via an alkyl group having 1 to 3 carbon atoms, a saturated or unsaturated or alkylene group or (C 1 -C 3) -alkyl bonded aryl or heteroaryl groups, the aryl and heteroaryl groups themselves being free of aryl or heteroaryl radicals.

The radicals R and R @ ^- are identical or different and denote water íkovv hydrogen, alkyl of 1-1 (1 carbon atoms, preferably alkyl having 1 to 6 carbon atoms, aryl

An aryl or heteroaryl group bonded via an alkyl group having 1 to 3 carbon atoms, a saturated or unsaturated or alkylene group having 1 to 3 carbon atoms, the aryl and heteroaryl groups themselves being free of aryl substitution or heteroaryl radicals, or the radicals R ² and R @ ²³ together represent a group CH2CH2OCH2CH.-,, CH2CH2NR ²⁶ CH? CH ₂ or (CH _{2) 36} and the radical R @ ² represents hydrogen, alkyl having 1 to 10 carbon atoms, preferably an alkyl group having 1 to 6 carbon atoms, an aryl group or a heteroaryl group, or an aryl or heteroaryl group bonded via an alkyl group having 1 to 3 carbon atoms, a saturated or unsaturated or alkylene group having 1 to 3 carbon atoms, the aryl and heteroaryl groups the groups themselves may not be substituted with aryl or heteroaryl radicals.

In one preferred embodiment of the process according to the invention, the compounds of the formula R @ 5 SH are used as lithium thiolates or react to lithium thiolates in or before reaction I.

In one preferred embodiment of the process according to the invention, before the reaction I, butyllithium (BuLi) is used to react the compounds of formula R ^ SH to 1-lithium thiolates, preferably in an equivalent ratio of BuLi: R ^ SH between 1: 5 and 1:20 , in particular 1:10, and reacted with R 1 SH and / or the reaction is carried out at temperatures < 0 ° C and / or in an organic solvent, in particular toluene, ether, THF or DCM, especially in THF.

• 0

0

0 0 «

In one preferred embodiment of the process according to the invention, at the start of reaction I the reaction temperature is <0 ° C, preferably lies between -70 ° C and -80 ° C, in particular at -78 ° C, and during reaction I the temperature is brought to room temperature or at the beginning of the reaction T the reaction temperature is <0 ° C, preferably lies between -30 ° C and -20 ° C, especially at -25 ° C and during reaction I the temperature is brought to a temperature between -20 ° C and -10 ° C, especially at -15 ° C.

In one preferred embodiment of the process according to the invention, the reaction I is carried out in an organic solvent, preferably in toluene, ether, THF or DCM, in particular in THF, optionally in a non-polar solvent, particularly in DCM or toluene. , preferably with use and with cooling.

In one preferred embodiment, the diastereomers are reacted by preparative HPLC or crystallization with a pentane / ethanol (10: 1) solvent.

In one preferred embodiment of the process according to the invention, the separation of the enantiomers is carried out before the separation of the diastereomers.

In one preferred embodiment of the method according to the invention:

R ¹ represents alkyl of 1 to 6 carbon atoms, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted;

R @ 1 represents alkyl of 2 to 9 carbon atoms, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted;

• 4 4 4 4 preferably r! represents alkyl having 1 to 2 carbon atoms, mono- or polysubstituted or unsubstituted, in particular methyl or ethyl, and

R 'is alkyl of 2 to 9 carbon atoms, preferably alkyl of 2 to 7 carbon atoms, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted, in particular ethyl, propyl, n-propyl, i-propyl, butyl, n-butyl, i-butyl, tert-butyl, pentyl, hexyl or heptyl, especially?

R is methyl and R is n-butyl.

In one preferred embodiment of the process according to the invention, the following applies:

R 6 is selected from alkyls having 1 to 3 carbon atoms, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; preferably methyl or ethyl.

In one preferred embodiment of the process according to the invention, the following applies:

R ⁴ is selected from alkyl of 1 to 6 carbon atoms, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; phenyl or thiophenyl, unsubstituted or mono- (preferably OCH ₃ , CH ₃ , OH, SH, CF ₃ , F, Cl, Br or i) substituted; or via nasvceny CH ₃ - Phenyl bonded, unsubstituted or monosubstituted (preferably with OCH-CH _3, OH, SH, CFj, F, Cl, Br or 1) -substituted;

It is preferably selected from alkyls having 1 to 6 carbon atoms, saturated, unbranched and unsubstituted, in particular methyl, ethyl, propyl, n-propyl, i-propyl, butyl, n-butyl, i-butyl, tert- butyl, pentyl or hexyl; phenyl or thiophenyl, unsubstituted or monosubstituted (preferably OCH 1, CH 2, OH, SH, CF 3, F, Cl, Br or I); or via saturated CH 2 - bonded phenyl, unsubstituted or once (preferably OCH 2 -,

CH3, OH, SH, CF3, F, Cl, Br or I) substituted, especially selected from methyl, ethyl or benzyl, unsubstituted or singly (preferably OCH3, CH3,

OH, SH, CF3, F, Cl, Br or I) substituted,

In one preferred embodiment of the process of the invention, the thiolate is used stoichiometrically, TMSCl is used and / or the chiral proton donor R * -H is used, or compound 30 is modified with sterile-intensive (large) groups prior to reaction I, preferably TBDMS.

In one preferred embodiment of the method of the invention, the compound of formula 31 is ethyl 3-ethylsulfanyl-2-formylamino-3-methyloctanoic acid or ethyl 3-benzylsulfanyl-2-formylamino-3-methyloctanoic acid, the compound of formula 30 is ethyl 2 -formylamino-3-methyloct-2-enanoic and R 5 SH is ethylmercaptan or benzylmercaptan.

Further preferred embodiments of the method according to the invention are further conditions and embodiments of the Michael addition as further illustrated herein.

Another object of the invention is a compound of formula 31

where

R 1, R 2 and R 3 are independently selected from alkyl of 1 to 10 carbon atoms, saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted; aryl or heteroaryl, in each case unsubstituted or mono- or poly-substituted;

* indicates stereoselective center and

R ⁴ is selected from alkyl of 1 to 10 carbon atoms, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; saturated or unsaturated, unsubstituted or mono- or poly-substituted cycloalkyl of 3 to 8 carbon atoms; aryl or heteroaryl, in each case unsubstituted or mono- or poly-substituted; or saturated or

unsaturated alkyl group having 1 to 3 carbon atoms of the bonded aryl, cycloalkyl having 3 to 8 carbon atoms or heteroaryl, in each case unsubstituted or mono- or multiply substituted;

in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of stereoisomers, in particular enantiomers or diastereomers, in any ratio in the mixture; in the form shown or in the form of its acids or bases or in the form of its salts, in particular physiologically acceptable salts, or in the form of its solvates, in particular hydrates.

The term salt refers to any form of the active ingredient according to the present invention in which it takes an ionic form, is optionally charged and is associated with a counterion (cation or anion) or is present in solution. This also includes complexes of the active ingredient with other molecules and ions, in particular complexes which are complexed via ionic interaction. In particular, this refers to physiologically acceptable salts with cations or bases and physiologically acceptable salts with anions or acids.

For the purposes of the present invention, physiologically acceptable salts with cations or bases are understood to be salts of at least one of the compounds according to the invention - mostly (deprotonated) acid - as an anion with at least one, preferably inorganic, cation which are physiologically acceptable, humans and / or mammals. Particularly preferred are the alkali metal or alkaline earth metal salts, but also ammonia, especially sodium or di-sodium, potassium or dipotassium, magnesium or calcium salts.

For the purposes of the present invention, physiologically acceptable salts with anions or acids are to be understood as meaning salts of at least one of the compounds according to the invention mostly, for example on nitrogen, protonated as a cation with at least one anion, which are physiologically acceptable. or mammals. In particular, it is meant within the meaning of the present invention a salt. formed with a physiologically acceptable acid, namely a salt of the corresponding active substance with inorganic or organic acids which are physiologically acceptable, especially when used in humans and / or mammals. Examples of physiologically acceptable salts of certain acids are salts with hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid. gluramic acid, 1,1-dioxo-1,2-dihydro-lb6-benzoles d] isothiazol-3-one (saccharinic acid), monomethylsebacic acid, 5-oxopropoline, hexane-1-sulfonic acid, nicotinic acid, 2-aminobenzoic acid, 3-aminobenzoic acid, 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, α-liponic acid, acetylglycine, acetylsalicylic acid, hippuric acid and / or aspartic acid. The hydrochloride salt is particularly preferred.

In one preferred form of the compounds of the invention:

R ¹ represents alkyl of 1 to 6 carbon atoms, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted, and γ>,

R 'represents alkyl of 2 to 9 carbon atoms, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted;

preferably r! represents alkyl having 1 to 2 carbon atoms, mono- or polysubstituted or unsubstituted, in particular methyl or ethyl; O

R is alkyl of 2 to 9 carbon atoms, preferably alkyl of 2 to 7 carbon atoms, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted, especially ethyl, propyl, n-propyl, i-propyl, butyl, n-butyl, i-butyl, tert-butyl, pentyl, hexyl or heptyl, in particular

Ί 2 R is methyl and R is n-butyl,

In one preferred form of the compounds of the invention:

R 6 is selected from alkyls having 1 to 3 carbon atoms, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; preferably methyl or ethyl.

In one preferred form of the compounds of the invention:

R ⁴ is selected from alkyl of 1 to 6 carbon atoms, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; phenyl or thiophenyl, unsubstituted or singly (preferably ·· »· *

• · *

OCH ₃ , CH ₃ , OH, SH, CF 3, F, Cl, Br or I) substituted; or unsubstituted or saturated (via OCH ₃ , CH ₃ , OH, SH, CF ₃ , F, Cl, Br or I) saturated saturated CH 3 - phenyl; Preferably

R ⁴ is selected from alkyls having 1 to 6 carbon atoms, saturated, unbranched and unsubstituted, especially methyl, ethyl, propyl, n-propyl, i-propyl, butyl, n-butyl, i-butyl, tert-butyl, pentyl or hexyl; phenyl or thiophenyl, unsubstituted or mono- (preferably OCH ₃ , CH ₃ , OH, SH, CF ₃ , F, Cl, Br or I) substituted; or via saturated CH 2 - bonded phenyl, unsubstituted or once (preferably OCH 2 -,

CH ₃ , OH, SH, CF ₃ , F, Cl, Br or I) substituted, especially

R ^{4 is} selected from methyl, ethyl or benzyl, unsubstituted or once (preferably OCH ₃ , CH ₃ ,

OH, SH, CF ₃ , F, Cl, Br or I) substituted.

In one preferred form of the compounds of the invention, the compound is selected from

3-ethylsulfanyl-2-formylamino-3-methyloctanoic acid ethyl ester, or

3-Benzylsulfanyl-2-formyl-amino-3-methyl-ethyl ester; tanové.

The compounds according to the invention are pharmacologically active, in particular as analgesics and toxicologically harmless, so that a further object of the invention are medicaments containing the compounds according to the invention as well as optionally suitable additives and auxiliaries and / or optionally other active substances. Furthermore, another object of the invention is the use of the compounds according to the invention for the manufacture of a medicament for the treatment of pain conditions, in particular neuropathic, chronic or acute pain, epilepsy and / or migraines, as well as corresponding methods of treatment.

The following examples are intended to illustrate the invention without limiting it.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Synthesis description

The target 32/33 molecule is to be produced by Michael addition. Figure 14 shows a retrosynthetic analysis of the starting material 34 needed for this batch:

Michael addition H ₃ C '- ->

+ RSH 35/36 h ₃ c.

R

0

32/33 ^H V 'Cli catalytic control (E, Z) -34 by external chiral ligand

9.11-R = Bn 10.12-R = Et

H _and C '

CH,

N C

Figure 14

Retrosynthetic follow-up of the starting material 34 for the S-analog Michael addition, wherein R in compounds 32 and 35 is benzyl and in compounds 33 and 36 is ethyl • φφφ φ φφφ

The 2-formylaminoacrylic acid ester 34 is to be prepared by an olefinization reaction from ketone 37 and ethyl isocyanic acid ester 38.

Figure 15 shows the synthesis method to prepare:

Figure 15: Planned synthesis to prepare isocyanate 38

In the planned synthesis (38), glycine (39) is to be esterified with ethanol in the first step to form glycine ethyl ester (40). This is formalized with methyl formate for aminofunction to give the formylamino ester (41). With formation of ethyl isocyanic acid ester (38), the formylamine function of the resulting 2-formylaminoacetic acid ethyl ester (41) is converted to phosphoryl chloride by an isocyanate function.

Example 2

Production of auxiliary chiral reagent: (S, S) -1,2-dimethoxy-1,2-diphenylethane

1. NaH, Reflux, 1 n, THF

2. MezSOq, RT, 17h

72%

Figure 16: Production of chiral dimethyl ether 4344

The production of the chiral dimethyl ether (43) is carried out according to the prescription of K. Tomioka et al. (see Figure 16) [34]. Into this, excess NaH is purified in THF, (S, S) -hydrobenzoin (42) in THF is added at room temperature and briefly heated to reflux. After 30 minutes the white, solid mass was stirred for a further 16 hours at room temperature. After working up and recrystallization from pentane, (S, S) -1,2-dimethoxy-1,2-diphenylethane (43) is obtained as colorless needles in a yield of 72%.

Example 3

Production of ethyl isocyanate

The starting compound of the synthesis of ethyl isocyanate (38) is prepared by the synthesis method shown in Figure 17:

NH

OH ² 39

90%

EtOH, SOCt ₂ , Δ

NH; HCl

NO! ₃ , HCCl ₂ E1, TsOH Δ

90%

Figure 17: Method for the synthesis of ethyl isocyanate (38) with thionyl chloride and an organic solvent, for the time of excess ethanol and as a solid. After giyeinethvlester as 97% in colorless form

Here, glycine (39) is heated with ethanol, which also functions as reflux for 2 hours. Removal of the thionyl chloride left the crude ester recrystallized from ethanol to give the hydrochloride (40) in a yield of 90 to needle solid.

Glycine ethyl ester hydrochloride (40) with slightly modified synthesis according to C.-H.Vong et al. [35] formyl on aminofunctional. Here, the glycine ethyl ester hydrochloride (40) is suspended in formic acid methyl ester, and toluene sulfonic acid is added in a catalytic amount. It is heated to reflux, triethylamine is then added dropwise and the reaction mixture is further refluxed. After cooling the reaction mixture, the precipitated ammonium chloride salt is filtered off. The remaining ethyl formate and triethylamine were removed from the filtrate and the crude ester was obtained as an orange oil. Distillation gave 2-formylamino-acetic acid ethyl ester (41) in a yield of 73-90% as a colorless liquid.

The transformation of a formylamino group into an isocyanate group is carried out according to the prescription of I.Ugi et al. [36]. The ethyl ester of 2-formylaminoacetic acid (41) in diisopropylamine and dichloromethane is mixed with phosphoryl chloride while cooling. After the addition was complete, warm to room temperature and subsequently hydrolyze the reaction with 20% sodium bicarbonate solution. Ethyl isocyanic acid ester (38) is obtained after work-up and purification by distillation in a yield of 73-79% as a pale yellow oil sensitive to light yellow oil.

• 44 ···

9 * 9 9

By using phosphorus chloride it was possible to circumvent the reaction with the hard-to-treat phosgene. At this stage, a loss in yield of about 10% had to be calculated according to literature [37], [38]. Despite these three steps, a total yield of 65% was achieved, with the first two steps being easy to carry out in large batches up to 2 moles. In contrast, the last step can only be carried out in small batches of up to 0.5 moles due to the large amounts of solvent and the high reactivity of the phosphoryl chloride.

Example 4

Production of (E) - and (Z) - 2-formyl amino-3-methyl-oct-2-enoic acid ethyl ester

The preparation of (E) - and (Z) -2-formylamino-3-methyl-oct-2-enoic acid ethyl ester (34) is carried out according to the prescription of S. S. Kopkop et al. J, [40] The isocyanic acid ethyl ester (38) is then deprotonated in situ with tert-butano and then added dropwise thereto after stirring for 30 minutes.

By adding an equivalent amount of potassium in the α-position. flow of 2-heptanone (37.) in THF. The reaction was quenched with glacial acetic acid.

The 2-formylamino-3-methyl-oct-2-enoic acid ethyl ester (34) is formed in each case in (E) - and (Z) - mixtures, these mixtures being easily separated by chromatography. The total yields of purified and separated (E) - and (Z) -isomers is 73% as a colorless solid.

In this reaction, which Schollkopf ⁴¹ called formylaminomethyleneization of the carbonyl compounds, is replaced in one step, the ketone oxygen of the form of the lamino-alkoxycarbones in the form of β-substituted.

The reaction is based on Figure 18.

The methylene group is formed and the .alpha.-formylaminoacrylic acids are formed.

1. K-T-Butylate, -20 ° C, THF

O 2,2-Heptanone (37). -20 ° C -> RT {o ch ₃

NC 33 ester below 1 e

+ K-fert.-butylate -BuOH

+ H *

-K ⁺

Figure 18: Mechanism of formylam inomethylenization of carbonyl compounds according to Schollkopf

In this case, the isocyanic acid ethyl ester 38 is first deprotonated with potassium tert-butylate in the α-position. The carbanion is then nucleophilically attached to the carbonyl carbon atom of ketone 37. After several intramolecular transitions of the negative charge and subsequent protonation, β-substituted acid esters of the L-α-form of the lamine-noakry are formed 3 4.

• · · φ · · · «·«

Since ethyl 2-formylamino-3-methyloct-2-enoic acid ethyl ester (34) is always formed in the (E) - / (Z) - mixture, the question of the effect of temperature on the (E) - / (Z) ratio arises.

Table 4: Influence of reaction temperature on (E) - / (Z) ratio

Reaction temperature Ratio (E) - / (Z) ^[a] 0 ° C to room temperature 57/43 -40 ° C to room temperature 63/37 -78 ° C to room temperature 62/38

as determined by C-NMR

The effect of temperature on (E) - / (Z) ratio can be seen from Table 4. The reaction is carried out under the above conditions. Only the initial temperatures change.

Obviously, the temperature has little effect on the (E) - / (Z) ratio. However, since both isomers are required for synthesis, a balanced ratio at about 0 ° C is preferred, since both isomers can be obtained by chromatography in approximately equal amounts.

The assignment (E) - / (Z) is carried out according to li. Schol 1 kopf ³⁹ , according to which the protons in the β-standing methyl group of the isomers (Z) absorb at a higher poLe intensity than the protons (E) r 43 1 of the ^{1 J} isomer.

Example 5

Michael's addition with thiols as donors • «φ φ <<<<<<• •

Α)

Experiments with thiolates as catalysts

Since Michael's addition of thiols to ethyl 2-formylamino-3-methyl-oct-2-enoic acid ethyl ester (34) does not proceed without catalysts, the procedure of T. Naito et al.

[44.

Rt SH 35.3

Figure 19: Thiolate-catalyzed Michael addition mechanism [44]

In this process, a mixture of thiol and l-lithium umtbiolate in a ratio of 10; 1 before addition of 2-formylaminoacrylic acid ethyl esters 34. The reaction taking place according to the mechanism of Figure 19 názorněného ^ ⁴⁴ L After the addition of thiolate or 36 to 35, ethyl 2-formyl amino-3-methylquinoline 1 - ok t - 2 - enovč f (E, Z) 34] At the β-position, this adduct 44 is protonated directly by the thiol present in excess to form the Michael adduct 32.33.

To form the Michael adduct 32.33, 0.1 ♦ · 9 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · · 4 equivalent of BuLi in THF and at a temperature are introduced. 10 equivalents of thiol are added at 0 ° C. Thereafter, dissolved in THF at low temperature at (E) or (Z) -34, and slowly warmed to room temperature. After hydrolysis with 5% sodium hydroxide solution and column chromatography, 32.33 was obtained as a colorless, viscous oil. which is a mixture of diastereomers.

Table 5 shows the synthesis described:

an overview of Michael's adducts produced

Table 5: Michael adducts produced

Edukt Thiol T [° C] Produk t dr ^a de [%] ^a Výě- žek (Z) -34 35 -78 ° C to TM 32 58:42 16 83% (Z) -34 35 -25 ° C to -15 ° C 32 59:41 18 98% (E) -34 35 -78 “C to TM 32 41: 59 18 79% (Z) -34 36 -78 ° C to TM 33 57:43 14 82%

TM room temperature

Ί A ^a Determined chromatographically by @ 1 C-NMR

As can be seen from Table 5, although pre-targeting was selected by selecting 2-formylamino-3-methyl-oct-2-enoic acid ethyl ester (Z) -34 or (E) -34, only the preferred diastereoisomer was determined. In THF it was not possible to achieve a better pre-routing with de> 18%, since the reaction in this medium starts only at> 20 ° C and even at higher temperatures better control cannot be expected.

··· ·· * · ··· * 0 * ··· * • · 0 * 00 0 0 * • · · * 0 ** 0 0 * *

The threo / erythro 32 diastereomers can only be separated by preparative HPLC chromatography. It has been found that the threo-diastereomer (threo) -32 is a solid, the erythro-di astereomer (e rythro) -32 is a viscous liquid.

Attempts have been made to separate the threo- / erythrodiastereomers by crystallization. The mixture of diastereomers 32 is dissolved in a small amount of pentane / ethanol (ca. 10: 1) and cooled to -22 ° C for at least 5 days, during which time the diastereomer (threo) - 32 crystallizes as a solid. Thus, enriched diastereomers ('threo) -32 or (ervthro) -32 with an excess diastereomer of 85 to 96% for (threo) -32 or 62 to 83% for (ervthro) -32 are obtained.

B) Experiments with Lewis acids as catalysts

MX - Lewis acid

Figure 20: Lewis acid catalyzed Michael additions i

As shown in Figure 20, attempts have been made to catalyze Michael's addition of benzyl mercaptan to ethyl ester of 2-form Laminoacrylic acid (34) by addition of Lewis acid MX _n . For the activation of α, β-unsaturated esters by various Lewis acids to add thiols [ ₇₇ ] _are examples, in which case a postulated complex A or B would be formed in which the metal coordinates on the oxygen of the carbonyl group ( visa picture 21):

Complex A

Figure 21

Postulated Lewis acid complexes

This complex should activate the double bond so strongly that the reaction proceeds directly. The Lewis acids MX _n listed in Table 6 were tested in different solvents for their catalytic effect on this Michael reaction. The equivalent of 2-formylamino-3-methyl-oct-2-enoic acid ethyl ester 34 in THF or DCM is always introduced and the equivalent of dissolved or suspended Lewiasic acid is added at 0 ° C. 1.2 equivalents of benzyl mercaptan was then added dropwise and warmed to room temperature after 2 hours. Partially, the batches were heated to reflux if the start of the reaction was not discernible after one day.

• · · v

Table 6: Lewis acids tested for catalysis of Michael addition

Lewis acid MX _n Solvent Temperature T Conversions ^a TiCl ₄ DCM TM after 18 hours no conversion Ti (Oi-Pr) ₃ Cl THF TM after 18 hours no conversion YbTf ₃ DCM TM no conversion after 3 hours YbTf ₃ THF 1 day TM and 1 day reflux no conversion after 2 days _ ( YC1 ₃ DCM TM no conversion after 3 days SnTf ₂ DCM TM after 3 days no rust cans ZnTf ₂ DCM TM after 3 days no rust cans ZnCl ₂ THF TM after 4 days no rust cans SnCl ₄ DCM 1 day TM and 1 day reflux no conversion after 2 days SnCl ₄ THF 1 day TM and 1 day reflux no conversion after 2 days BF ₃ . E t0 ^> DCM TM no conversion after 2 days AlCi ₃ THF TM no conversion after 2 days

determined by DC-samples optionally by NMR

Only in the case of titanium tetrachloride it is possible to detect color changes, which can be derived from the formation of: • 0 • 00 · • · 0 · 0 * • * 000 0 0 0 000 0 0 0 0 0 0 0 0 0 0 ♦ 00 000 00 0 · Complex. In contrast to all other Lewis acids, complex formation was not apparent by the color change. None of the Lewis acids tested showed a catalytic effect, since in all cases up to a reaction time of 3 days no conversion could be detected and the starting materials could be recovered completely.

C)

Experiments with catalysis of Lewis acids with addition of bases

Michael's addition of thiols to α, β-unsaturated ketones can be catalyzed by the addition of bases (e.g., triethylamine) as described in Section 1.2.4-4 -45. In doing so, the Bronstedt base increases the nucleophilicity of the thiol, which is sufficiently large to start the reaction.

In the reaction of equimolar amounts of ethyl 2-formylamino-3-methyl-oct-2-enoic acid 34, benzyl mercaptan (35) and triethylamine in THF, no catalysis effect was observed at reaction temperatures up to 60 ° C. Starting materials could be recovered.

MX _n : Lewis acid

Figure 22: Base and Lewis acid catalysis

It is therefore possible to combine the idea of Lewis catalysis

0

0 * 0 00000 0 0 · 0 * 00 0 0 0 0 0 ·

0000 · 0 0 0 0 0 0 • 0 00 00 000 0 0 · · Acids (listed in Section 2.6.2) with base catalysis (see Figure 22), since catalysis by Lewis acids or Bronstedt bases alone is not functional.

For the base and Lewis acid combinations shown in Table 7, an equivalent of 2-formyl-amino-3-methyl-oct-2-enoic acid ethyl ester (34) in each solvent was always added and a solution of 1.2 equivalents of benzyl mercaptan (35) and 1 equivalent was added dropwise. of said base at 0 ° C. After two hours, warm to room temperature and stir for an additional three days. No conversion could be detected for any of the base and Lewis acid combinations. Even in the case of a batch where benzyllithium thilate in combination with titanium tetrachloride was used as the base, no conversion was observed, although without the addition of titanium tetrachloride it was possible to achieve complete conversion already at 0 ° C.

Table 7: Testing combinations of bases and Lewis acids for catalysing Michael addition

Lewis acid to Base Solvent Conversions ^a - Net ₃ THF - TiCl ₄ Net ₃ THF - TÍC1 ₄ BnSL i THF - T1C1 ₄ BnSLí THF + TÍC1 ₄ Net ₃ DCM - A1C1-J Met ₃ THF -

and determined by DC-samples

D) VIiv solvents

The question of a suitable solvent arises if, under the reaction conditions described in section 2.6.1, a possible higher de-value is to be achieved by changing the solvent.

Table 8: Effect of solvent in addition of benzylmercaptan (35) to (E.Z) -34,

Eduk t Roz- Generation Temperature Time reaction dr ^a de [%] ^a (Z) -34 THF -20 ° C to -15 ° C 2 h 59:41 18 <Έ) -34 THF -78 ° C to TM 2 h 41: 59 18 (Z) -34 Ether -25 ° C to -5 ° C 2 h 63:27 26 (Z) -34 Toluene 0 C to TM 16 h 72:28 44 (E) -34 Toluene 0 “C to TM 16 h 32:68 36 (Z) -34 DCM 0 “C to TM 7-17d ^b 75: 25 50 (E) -34 DCM 0 ° C to TM 7-17 ^p 25: 75 50

TM room temperature ^and determined by chromatography using a ^J C-NMR ^b Only 50% conversion

As can be seen from Table 8, it is possible to increase the de-value by selecting another solvent. A noticeable increase in non-polar solvents such as toluene and DMC can be recognized.

The de-value was 50%, but the reaction time increased from 2 hours in THF to 17 days in DCM. It was also possible to detect only 50% conversion in DCM after 7 to 17 days.

♦ 0 * 0

E)

Attempts to control the complexation of Michael's donor

(2) -34 (K, S) -32

Figure 23: Michael addition with control by chiral diether (S, S) -43.

The aim is to control the Michael addition by adding a chiral compound (see Figure 23) to a thiolate catalyzed reaction (see Section 2.6.1).

The control of the reaction is carried out according to Tomiok et al. In this case, benzyl lithium thiolate is used only in catalytic amounts. By adding chiral dimethyl ether (S, S) -43, Lithium Thiolate should compLex to control its effect. Thus, instead of a mixture of diastereomers produced according to Chapters 2.5.1 and 2.5.4, only one diastereoisomer should be enantioseectively.

1 32 1

It is believed that the ^{LJ chelate} shown in Figure 24 is formed. In it, lithium thiolate is complexed by both oxygen atoms of dimethyl ether. At. The attack of coordinate 50 is also oxygen of the carbonyl group Michael acceptor 34 to the central lithium atom, thereby controlling the reaction.

CH ₃

Figure 24: Postulated Michael addition control complex by addition of (S, S) -43 dimethyl ether

Table 9: Experiments with chiral dimethyl ether (S, S) -43 control

Edukt Roz- Generation Chiráíní diether (S, S) -43 Time reaction dr ^a ee [%] ^b diastereomers (Z) -34 THF - 2 h 59:41 0 (Z) -34 Ether 0.12 eq. 2 h 63: 37 5 - 7 (2) -34 Toluene 0.12 eq. 16 h 71: 29 4 12) -34 Toluene - 16 h 72:28 1-4 (Z) -34 DCM 0.12 eq. 16 h 75:25 1 - 9 (Z) -34 DCM - 17 d 79: 21 4 - 6 (E) -34 Toluene 0.12 eq. 16 h 30: 70 1 (E) -34 Toluene - 16 h 32:68 0 (E) -34 DCM 0.12 eq. 7 d 25: 75 5 - 7 (E) -34 DCM - 7 d 32:68 1-6 (E) -34 THF - 2 h 41:59 0

^a Determined by chromatography using @ 1 C-NMR b by anal. HPLC

Experiments with dimethyl ether (S, S) -43 were carried out in ether, DCM and toluene. 0.1 equivalents of BuLi is introduced at 0 ° C and 10 equivalents of benzyl mercaptan 35 are added. To this is added 0.12 equivalents of dissolved dimethyl ether (3.51-43. However, it is not possible to detect complex formation by discoloration. 30 minutes later, the equivalent of ethyl 2-formate of lamine-3-methyl-oct-2-enoic acid ( 34) at 0 ° C. The reaction was terminated at the indicated times by addition of 5% sodium hydroxide solution.

Excess diastereomers were determined by @ 1 H-NMR spectrum after purification by column chromatography. Excess enantiomers were detected after recrystallization of the diastereomer (threo) - 32 from pentane / ethanol by analytical HPLC on a chiral stationary phase.

As shown in Table 9, no chiral induction of Michael addition could be detected after addition of the chiral dimethyl ether, since the measured enantiomeric excesses were within the accuracy of the HPLC. This is because the purified diastereomers are contaminated with other diastereomers and all 4 isomers together cannot be measured with separate baselines.

Example 6

Summary i · · · ·

In the context of the present invention, a synthesis process for the preparation of (E, Z) -formylaminoacrylic acid (E, Z) -34 esters was first developed. This was accomplished by a four-step synthesis based on glvcin (39). After esterification, N-formInci, condensation of N-formylaminofunction and olefinization, E (Z) -34 is obtained in a total yield of 47% and with a (E / Z) ratio of 1: 1.3 (see Figure 25).

degree

OH

NH47%

39

Figure 25: Synthesis of (E, Z) -2-formylaminoacrylic acid esters (E, Z) -34

The synthesized esters of (E, Z) -2-formaminoacrylic acid (E.Z) - 34 should be mercapped by Michael addition. By adding 0.1 equivalents of 1 ithium thiolate, the reaction can be catalyzed.

In order to enable enencioselective control by means of chiral catalysts, the use of various catalysts which may subsequently be provided with chiral ligands has been investigated.

Lewis acids, Bronstedt bases and combinations thereof in various solvents were tested for their catalytic effect (see Figure 26). However, no suitable catalyst systems have been found for the desired Michael addition.

Figure 26: Catalysis experiments of S-analogs of Michael addition

Michael addition of the catalysed thiolate produces a mixture of both diastereomers. Solvent exchange increased the diastereomer excess using (Z) -34 from 17% (THF) over 43% (toluene) to 50% (DCM). Starting from (E) -34, comparable de-values were achieved with the reverse diastereomer ratio. To achieve a satisfactory conversion, reaction54 · «· · • ·

However, the start-up time with the de-value also increased from 2 hours (THF) to 17 days (DCM).

By crystallizing threo-diastereomers of threo (32) from pentane / ethanol (10: 1), the threo- and erythro-diastereomers 32 could be further purified up to a de-value of 96% for threo- (32) and 83% for erythro- ( 32).

Based on the successful catalysis with 0.1 equivalents of thiolate attempts were made to drive ^ ³ ^ ·] attack of the thiolate addition of the chiral diether (S, S) - 1,2-dimethoxy-1,2-diphenylethane [(S, S) -431. The reaction was carried out in non-polar solvents. However, no effect of diether (SS) -43 on the control of the reaction has so far been observed.

Example 7

Use of TMSC1

Since the separation of diastereomers developed in this invention works well, the thiolate can be used stoichiometrically, as shown in Example 5, and the adduct is preferably captured by TMSC1 as the enolether 45. By protonating this adduct 45 with a chiral proton donor R * -H center (see Figure 27).

· ♦ »

separation of diastereomers

32, pure enantiomers

Figure 27

Control of the center with the subsequent separation of diastereomers

The two enantiomeric diastereomers formed can be separated by crystallization as described. In this way of control, all four stereoisomerves are readily available.

Example 8

Use of sterically demanding groups

A second possibility of controlling the Michael addition is intramolecular control using sterically challenging groups, preferably TBDMS. These can be controlled by the method according to D.Enders and B. Lohray] t47] α-Silylketone 47 made from starting acetone (46) is then reacted with ethyl isocyanate (38) to give 2-formylamino-3-methyl-4- (t-butyldimethylsilyl) -2-octenic acid ethyl ester (E) - 48 and (Z) -48 (see Figure 28).

O

AT

H ₃ r xh ₃

1. SAMP

2. LPA, TBDMSC1

3. LDA, n-8µBr

4. O ₃

H ₃ C '

CH ₃

TBDMS

(Z) -4S

NC

OEt

Figure 28: Introduction of the control TBDMS group (E) -48 or (Z) -48 then reacted by Michael addition with thiol, the reaction being controlled by the TBDMS group and the (E / Z) -isomers. The control TBDMS group can be removed again by the method T.Otten ^ ¹² ] with n-BuNF ₄ / NH ₄ F as the cleavage group.

Γ12 1 reagent ii, where publication of T.Otten ¹ - is part of the application. Also in this way there is the possibility to synthesize all four isomers independently of one another.

Since the aforementioned alternative synthesis offers the possibility of asymmetric catalysis in the protonation of silylene ether 45, this method is a better alternative. The second • · · · * ·

alternatively, there is still a problem with the cleavage of the silica group, since under the cleavage conditions also the N-formyl group is often cleaved to form the hydrofluoride.

Example 8

Experimental conditions:

Notes to preparative work

A) Shielding gas technology

All air and moisture sensitive reactions are carried out in evacuated, heated flasks closed with an orifice in an argon atmosphere.

Liquid components or components dissolved in solvents are dosed using V2A cannula plastic syringes. The solids are replenished in a stream of argon.

B) Solvents

Pre-dried or pre-purified solvents were used for the finalization:

Tetrahydrofuran Four hours reflux over calcium hydride and subsequent distillation

Abs. tetrahydrofuran 2 hours reflux of pretreated methylene chloride THF over sodium-lead alloy under argon followed by 4 hour refLux distillation over calcium hybrid and subsequent distillation through a 1 m packed column

···· · «·« * · · · · ··· 58 ······ · » ······ · · * t + · * · · · «« · · ··· Abs. Dichloromethane shaking of pre-treated dichloromethane with concentrated sulfuric acid, neutralization, drying, two hours reflux over calcium hydride under argon and subsequent distillation Pentane reflux for 2 hours, followed by distillation over 1 m packed column Diethylether reflux for two hours over potassium hydroxide and subsequent distillation over 1 m packed column Abs. diethyl ether 2 hours reflux over sodium-lead alloy under argon and subsequent distillation Toluene reflux for 2 hours over sodium wire and subsequent distillation over 0.5 m packed column Abs. toluene two hour reflux over the alloy sodium-lead and subsequent distillation Methanol 2 hour reflux over magnesium / magnesium methoxide and subsequent dest i lácy

C) Reagents used

N-Butyllithium (S, S) - (-) - 1,2-dienyl-1,2-ethanediol Argon Benzylmercapan Ethylmercaptan argon was collected from Linda n-BuLi was obtained as a 1.6 molar solution in hexane from Merck was taken from Aldrich was taken from Aldrich was taken from Aldrich «ι>« Φ * • φ φ φ * φ φ φ · * · · * φ

ΦΦ φ * «φ φφφφ Φ # · ΦΊΦ • ΦΦΦ

• Φ Φ • • •

ΦΦφ ΦΦ ΦΦ

2-Heptanone was purchased from Aldrich.

All other reagents were wound from Aldrich, Fluka, Merck and Acros or were available on site.

D) Checking the progress of the reaction

Thin layer chromatography is used to control the progress of the reaction as well as to detect it after column chromatography (see chapter 3.1.5). It is carried out on a glass plate coated with a layer of silica gel with a fluorescent indicator (Merck, Kieselgel 60, 0.25 mm layer). Detection is carried out by fluorescence (absorption of UV light at 254 nm) and also by immersion in the solution of mostain (5% (NH ₄ ) solution ₆ Mo ₇ 0 ₂₄ in 10% sulfuric acid (v / v) with addition of 0,3% Ce (SO ₄ ) 2) and subsequent heating in a hot air stream.

E)

Product cleaning

The purification of the substances is usually carried out by column chromatography in a glass column with a built-in glass frit with silica gel 60 (Merck, grain size 0.040-0.063 mm). The process is carried out at an overpressure of 0.01 to 0.03 MPa. The eluent is generally chosen such that the Rf value of the isolated substance is 0.35. The composition of the solvent mixture is measured volumetrically. The diameter and length of the column adapt to the problem of division and the amount of substance.

Some crystalline substances are also purified by recrystallization in suitable solvents or mixtures thereof.

• * · ·

F) Analytics

R

HPLC Gilson Abimed, Column: Hibar preparative ^r

Fertigsaule (25 cm x 25 mm) from Merck and UV detector ^ P ^^ analytical ^ H-NMR-spectroscopy ¹³ C-NMR-spectroscopy

2D-NMR spectroscopy Gas chromatography

IR spectroscopy

Mass spectroscopy Elemental analysis

Hewlett-Packard Column; Daicel OD, UV-detector

Varian GEMTNI 300 (300 MHz) and Varian ln 400 (400 MHz) with tetramethylsilane as internal standard Varian GEMINI 300 (75 MHz) and Varian ln 400 (100 MHz) with tetramethyl strength as internal standard Varian ln 400

Siemens Sichromat 2 and 3, FID detector, columns: OV-17-CB (Fused Silica, 25 m x 0.25 mm, ID),

CP-Force-8 (Fused Essential Oil, 30 m x 0.25 mm, ID)

a) measurement of KBr tablets: Perkin-Elmer FT / IR 1750

(b) measurement in solution: Perkin-Elmer FT / IR 1720X

Varian MAT 212 (El 70eV, Cl 100eV) Heraeus CHN-O-Rapid, Elementar Vario El

Melting points

Tottoli melting temperature apparatus Buchi 535.

G) Notes on analytical data

Yields

The yields refer to isolated purified products • φ · φ

Boiling point / pressure Said boiling points were measured in the apparatus with a mercury thermometer and are not corrected. The corresponding pressures were measured by analog measurements - whose sensors Ί NMR-NMR-spectroscopy delta chemical shifts are given in ppm against tetramethylsilane as internal standard and constant J bond in Hertz (Hz). The following abbreviations are used to describe the multiplicity of signals: s = singulet, d = doublet, t = triplet, q = quartet, quin = quintet, m = multiplet. K denotes the complex region of the spectrum. Br is preceded by wide signal @ ¹ H-NMR spectroscopy delta chemical shifts are given in ppm against tetramethylsilane as internal standard de-values Detection of excess diastereomer 1 Q (de) is carried out by C-NMR- spectra of compounds. This method utilizes different shifts of diastereomeric compounds in the bound proton spectrum IR spectroscopy The position of the absorbent bands (n) is given in cm ⁴ . The following abbreviations are used to characterize belts; vs = very strong, s = strong, m = medium, w = s.Low, vw = size very weak, br = six years Gas chromatography Retention rates of unexpanded are reported compounds in minutes. Then us-

0 0 *

Data on measurement conditions: column used, start temperature, temperature gradient, end temperature (always in ° C) and injection temperature T, if these temperatures deviate from standard temperatures (Sil 8:

_T = 270 ° C, OC-17 T = 280 ° C

Mass spectroscopy Mass data of fragments (m / z) are reported as a dimensionless number whose intensity is a percentage of the baseline to baseline peak (rel.int.). High intensity (> 5%) or characteristic signals are reported.

Elemental analysis Data in% by weight of the indicated elements. Samples of substances were considered authentic at ^delra C, H, N ^{with 0} ' ^5%

Example 10

General working rules

Preparation of glycinalkylester hydrochlorides [AAV 1]

1.2 equivalents of thionyl chloride are added to 0.6 ml of alcohol per mmol of glycine under ice-cooling at -10 ° C. After removal of the ice bath, 1 equivalent of glycine is added in portions. The mixture was heated to reflux for 2 hours. After cooling to room temperature, excess alcohol and thionyl chloride were removed on a rotary evaporator. The white solid obtained is stirred twice in alcohol and this is again removed on a rotary evaporator in order to completely remove the adhering thionyl chloride.

»»

Preparation of Form Amino Acetic Acid Acyl Esters [AAV 2] Equivalent, Alkyl Glycine Hydrochloride Hydrochloride is suspended in 0.8 ml ethyl or methyl formate per mmol glycine alkyl ester hydrochloride. 130 mg of toluenesulfonic acid per mmol of glycine alkyl ester hydrochloride are added and heated to reflux. Then, 1.1 equivalents of triethylamine was added dropwise to the boiling solution, and the reaction solution was stirred at reflux overnight. After cooling to room temperature, the precipitated ammonium chloride salt is filtered off, the filtrate is evaporated to about 20% of the original volume and cooled to -5 ° C. The re-precipitated ammonium chloride salt is filtered off, the filtrate is concentrated and distilled at 100 Pa.

Preparation of Alkyl Isocyanic Acetate [AAV 3] Equivalent to Formylamino Acetic Acid Alkyl ester and 2.7 equivalents of diisopropylamine were taken up in DCM (10 mL per mmol Formylamino Acetic Acid Alkyl ester) and cooled to -3 ° C in an ice bath. Then, 1.2 equivalents of phosphoryl chloride was added dropwise, followed by stirring at this temperature for an additional hour. After removal of the ice bath and reaching room temperature, 1 ml of a 20% sodium carbonate solution per mmol of the aminoacetate of alkyl formate is carefully hydrolyzed. After about 20 minutes, strong foam formation is observed and the flask must be cooled with ice water. After stirring at room temperature for 60 minutes, additional water (1 mL per mmol · equivalent of 1 equivalent of formyl aminoacetic acid alkyl ester) and DCM (0.5 mL per mmol of formyl aminoacetic acid alkyl ester) were added. The phases are separated and the organic phase is washed twice with 5% sodium carbonate solution and dried over magnesium sulphate. The solvent was removed on a rotary evaporator and the remaining brown oil was distilled.

Preparation of (E) - and (Z) -2-formylamino-3dialkylprop-2-enoic acid alkyl esters [AAV 4]

1.05 equivalent of target of potassium butanolate in 0.7 ml of THF per mmol of isocyanic acid alkyl ester is cooled to -78 ° C. To this was added slowly a solution of 1.0 equivalent of alkyl isocyanate in 0.25 mL of THF per mmol and stirred at this temperature for 30 minutes (- pink colored suspension). A solution of 1.0 equivalent of ketone in 0.125 mL of THF per mmol is then added dropwise. After stirring at -78 ° C for 30 minutes, warm to room temperature (1 hour) and add 1.05 equivalents of glacial acetic acid (yellow solution) portionwise and stir for an additional 20 minutes. The solvent was removed on a rotary evaporator (bath temperature 40 ° C). The crude product was obtained as a solid. The solid was suspended in 1.5 ml diethyl ether per mmol and 0.5 ml water per equivalent was added. The clear phase was separated and the aqueous phase was extracted twice with diethyl ether. The combined organic phases were washed with saturated sodium bicarbonate solution and dried over magnesium sulfate. Removal of the solvent gave a waxy solid. Chromatography with diethyl ether / pentane (4: 1) as eluent separates (E) - and (Z) - products,

Preparation of 2-formylamino-3-dialkyl-3-alkylsulfanylpropanoic acid alkyl esters [AAV 5]

Place 0.1 equivalent of butyllithium in 50 mL of THF mmol and cool to 0 ° C. Then 10 equivalents of mercaptan are added dropwise. After stirring for 20 minutes, the solution was cooled to between -40 ° C and 0 ° C and one equivalent of 2-formylamino-3-dialkylprop-265-enoic acid alkyl ester in 5 mL of THF was slowly added. It was stirred at the set temperature for 2 hours and then warmed to 0 ° C and hydrolyzed with 5% sodium hydroxide solution. The phases were separated and the aqueous phase was extracted twice with diethyl ether. The combined organic phases were dried over magnesium sulfate and the solvent was removed on a rotary evaporator. The mercaptan used in excess can be separated by chromatography with DCM / diethyl ether (6: 1).

Example 11

Special working instructions and analytical data

A) (S, S) - (-) - 1,2-dimethoxy-1,2-diphenylethene (S, S) -43

140 mg of sodium hydride (60% in paraffin) were washed three times with pentane and dried in HV. It is then suspended in 5 ml of absolute THF. 250 mg (1.17 mmol) of (S, S) - (-) - 2,2-diphenyl-2,2-ethanediol (42) dissolved in 3 ml of THF are then added dropwise. After the addition, the mixture is stirred at reflux for 30 minutes and finally cooled to 5 ° C. 310 mg of dimethyl sulfate are added slowly dropwise and stirred for 30 minutes under ice-cooling. The ice bath was removed and the reaction was warmed to room temperature to give a viscous white mass that was stirred at room temperature overnight. The reaction was quenched by the addition of 5 mL of saturated ammonium chloride solution. The phases were then separated and the aqueous phase was extracted twice with diethyl ether. The combined organic phases were first washed with a saturated sodium bicarbonate solution and then with Brine and dried over magnesium sulfate. Removal of the solvent on a rotary evaporator gave a colorless solid which was recrystallized in pentane at -22 ° C. Dimethyl ether is obtained as colorless needles.

Yield: 204 mg (0.84 mmol, 72%)

Mp: 98.5 ° C (Lit: 99-100 ° C) ^[39]

GC; R _t = 3.08 min (OV-17, 160-10-260) 1 H-NMR spectrum (400 MHz, CDCl ₃ ):

δ = 7.15 (m, 6H, H _Ap ), 7.00 (m, 4H, U _Ar ), 4.31 (s, 2H, CHOCH ₃ ), 3.27 (s, 6H, CH ₃ ) ppm .

l ^ C-NMR spectrum (100 MHz, CDC1 _3):

S = 138.40 _{(Ar C>} J _Quart, 128.06 (4xHC _Ar), 127.06 (HC _{Ar para),} ^{8? '98} (£ _H3), 57.47 (HC0CH ₃₎ ppm.

IR spectrum (KBr -):

_v = 3448 (br m), 3082 (m), 3062 (m), 3030 (s) 2972 2927 2873 (s), 2822 (vs), 2583 (vw), 2370 (vw) 2179 (vw) , 2073 (m), 1969 (m), 1883 (m), 1815 (m), 1760 (w), 1737 (vw), 1721 (w), 1703 (w), 1686 (vw), 1675 (vw), 1656 (W) 1638 (m), 1603 (m), 1585 (m) (w), 1561 ( (w), 1545 (w), 1525 (vw) 1492 (s), 1452 (1), 1349 1308 (m), 1275 (w), 1257 (vw), 1215 (vs), 1181 (m), 1154 m 1114 (vs) 1096 (vs) 1028 (m), 988 (p), 964 (p) , 914 m 838 (s), 768 701 (vs), 642 (m), 628 (s), 594 515 (s) [cm ^-1 ]. MS (CI, isobutane): M / z [%] = 212 (M @ ⁺ +1 OMe, 16), 211; (M ⁺ -MeOH, 100), 165

(M ⁺ , Ph, 2), 121 (% M ⁺ , 15), 91 (Bn ⁺ , 3), 85 (M ⁺ - 157.8), (M ⁺ - 161.7), 79 (M ⁺ -) 163, 6), 71 (M ^& lt ^{; +} & gt ^; - 171.8).

Elementary analysis:

calculated: C = 79.31 H = 7.49 found: C = 79.12 H = 7.41

All other analytical data agrees with the data set out in Section 341 of the ^LJ Charter.

B) Glycine ethyl ester hydrochloride (40)

O

NH ₂ · HCl M = 139.58 g / mol

According to AAV 1, 1000 ml of ethanol was reacted with 130 g (1.732 mol) of glycine 39 and 247.3 g (2.08 mol) of thionyl chloride. Recrystallization from ethanol gave a colorless solid as needles, which was dried in HV.

Yield: 218.6 g (1.565 mmol, 90.4% of theory)

GC: R _t: 1.93 min (OV-17, 60-10-260)

^M.p .: 145 ° C (Li: 144 ° C) ^{[48] 1} H-NMR spectrum (300 MHz, CD 3 OD):

δ = 4.30 (q, J = 7.14, 2H, OCH 3), 3.83 (s, 2H, H ₂ CNH ₂ ), 1.32 (tr, J = 7.14, 3H, CH ₃ ) ppm.

⁴ ^ C-NMR (75 MHz, CD ₃ OD):

δ = 167.53 (C = O), 63.46 (OCH ₂ ), 41.09 (H ₂ CNH ₂ ), 14.39 (CH ₃ ) ppm.

analytical data agrees with lite68 data

All other races [48]

C) N-formylglycine ethyl ester (4a)

0 h ₃ c ^ o ^H Y

M = 139.58 g / moi ⁰

According to AAV 2, 218 g (1.553 mol) of glycine ethyl ester hydrochloride (40), 223 mg of toluenesulfonic acid and 178 g of triethylamine are reacted in 1.34 L of ethyl formate. After distillation at 100 Pa a colorless liquid is obtained.

Yield: 184.0 g (1.403 mmol, 90.3% of theory)

GC: R _x = 6.95 min (CP-Sil 8, 60-10-300)

Tv: 117 ° C / 1 mbar (Lit: 119-120 ° C / 1 mbar) ^{49 49} 1 H-NMR spectrum (400 MHz, CDCl ₃ ):

δ = 8.25, 8.04 (s, d, J = 11.81, 0.94 H, 0.06 H, HC = O),

4.22 (dq, J = 7.14, 3.05, 2H, (OCH ₂ )), 4.07 (d, J = 5.50, 2H, H ₂ CC = O), 1.29 (tr, J = 7.14, 3H, CH ₃₎ ppm.

l ^ C-NMR spectrum (100 MHz, CDC1 _3):

δ = 169.40 (0C = 0), 161.43 (HC = O), 61.55 (OCH ₂ ), 39.90 (H ₂ CNH ₂ ), 14.10 (CH ₃ ) ppm.

All other analytical data are consistent with the data given in Chapter 49 1 of the ^LJ Charter.

D) Isocyanic acid ethyl ester (38)

NC

M = 113.12 g / mol

According to AAV 3, 50 g (381 mmol) of formylglycinethyl ester 41, 104 g (1.028 mol) of diisopropylamine and 70.1 g (457 mmol) of phosphoryl chloride were reacted in 400 ml of DCM. After distillation at 500 Pa a slightly yellowish liquid is obtained.

Yield: 34.16 g (302 mmol, 79.3% of theory)

GC: R _t = 1.93 min (OV-17, 50-10-260)

Tv: 77 ° C / 5 mbar (Lit: 89-91 ° C / 20 mbar) ^{[50] 1} H-NMR spectrum (300 MHz, CDCl ₃ ):

δ = 4.29 (q, J = 7.14, 2H, 0¾), 4.24 (d, J = 5.50, 2H, H ₂ CC = O), 1.33 (tr, J = 7, 14, 3H, _CH3) ppm. l ^ C-NMR (75 MHz, CDC1 _3):

δ = 163.75 (OC = 0), 160.87 (NC), 62.72 (OCH ₂ ), 43.58 (H ₂ CNH ₂ ), 14.04 (CH ₃ ) ppm.

IR spectrum (capillary):

= _V 2986 (s), 2943 (w), 2426 (br vw), 2164 (vs, NC), 1759 (vs, C = 0), 1469 (w), 1447 (v), 1424 (m), 1396 (vw), 1375 (s), 1350 (s), 1277 (m), 1213 (m), 1098 (m), 1032 (m), 994 (m), 937 (m), 855 (m), 789 (br m), 722 (vw), 580 (m), 559 (w) [cm ^-.

MS (CI, isobutane):

M / z [%] = 171 (M ^& lt ^; + &^gt; isobutane, 6), 170 (M ^& lt ^; + &^gt; isobutane-1.58), 114 (M ^& lt ^; + ^& gt ;, 100), 113 (M ^& lt ^{; +} &^gt; ⁺ - 13, 2), 98 (M ⁺ - CH 3, 2), 87 (M ⁺ - C 2 H ₅ + 1, 1), 86 (M ⁺ - C ₂ H _5, 18), (M ⁺ - 29, 2 ).

* 0 * 0 · ·· * 0 · 0 00 0 »0 0 0 0 0 0 0 0 0

0 0 0 0 000 0

0 * 0 · 00 e 0000 · * 00 000 0 »00

All other analytical data are consistent with literature data 150]

E) (E) - and (Z) -2-Formylamino-3-non-ethyl-oct-2-enoic acid ethyl ester ((E, Z) - 34)

According to AAV 4, 15 g (132 mmol) of ethyl isocyanate are reacted 38. 15.6 g (139 mmol) of potassium tert-butanoate, 15.1 g (132 mmol) of heptan-2-one 37 and 8.35 g of 139 mmol ) glacial acetic acid.

Chromatography with diethyl ether / pentane (4: 1) as eluent separates (E) - and (Z) - products.

Yield: 11.52 g (50.7 mmol, 38.0% of theory) of (Z) -product

9.07 g (39.9 mmol, 30.2% of theory) (E) -product 1.32 g (5.8 mmol, 4.4% of theory) mixed fraction

F) (Z) -2-Formylamino-3-methyl-oct-2-enoic acid ethyl ester ((Z) - 34)

About • · ** »·

GC: R _t = 12.96 min (CP-Sil 8, 80-10-300)

Mp: 57 ° C (colorless, amorphous)

DC: = 0.32 (ether: pentane - 4: 1)

R f = 0.34 (DCM: ether - 4: 1)

The ratio of rotamers around the N-CHO bond is 65:35.

spectrum (400 MHz, CDC1 _3):

δ = 8.21, 7.95 (d, d, J = 1.38, 11.40, 0.65, 0.35 H, HC = O), 6.80, 6.69 (br s, br d, J = 11.40, 0.65, 0.35 H, HN), 4.22 (dq, J = 1.10 (dq, J = 1.10, 7.14, 2H, OCH ₂ )), 2.23 (dtr, J = 7.97, 38.73, 2H, C = CCH ₂ ), 2.20 (dd, J = 1.10, 21.7, 3H, C = CCH ₃ ), 1, 45 (dquin, J = 1.25, 7.97, 2H, CCH ₂ CH ₂ ), 1.30 (dquin, J = 4.12, 7.14, 4H, CH ₃ CH ₂ CH ₂ ), 1, 30 (m. 3H,

OCH ₂ CH ₃ ), 0.89 (tr, J = 7.00, 3H, CH ₂ CH ₃ ) ppm.

l ^ C-NMR spectrum (100 MHz, CDC1 _3):

S = 164.82, 164.36 (OC = 0), 159.75 (HC = O), 152.72, 150.24 (C = CNH), 120.35, 119.49 (C = CCH ₃ ) , 61.11, 60.89 (OCH ₂ ),

35.82, 35.78 (CH ₂ ), 31.80, 31.72 (CH ₂ ), 27.21, 26.67 (CH ₂ ), 22.45, 22.42 (CH ₂ ), 19, 53, 19.17 (C = CCH ₃ ), 14.18 (OCH ₂ CH ₃ ), 13.94, 13.90 (CH ₂ CH ₃ ) ppm.

IR spectrum (KBr):

⁼ v 3256 (vs) 2990 (v) 2953 (w), 2923 (m) 2872 (w) 2852 (w), 2181 (br vw), 1711 (vs, C = O), 1659 (vs, OC = O) 1516 (s), 146 5 1381 (s), 1310 (vs) , 1296 (vw), 1269 (m), 1241 (with), 1221 (s) 1135 (w), 1115 (vw), 1032 (vs) 1095 (s), 1039 (m) 884 (m), 804 ( m), 727 (vw), 706 (vw ) 590 (w), 568 ( vw) [cml]

MS (EI, 70eV):

24), 181 (M ⁺ 8), 156 (M ⁺ HC0 _of Et, 13), 152

M / z [%] = 227 (M ^& lt ^{; +} & gt ^; , 19), 182 (M ^& lt ^{; +} & gt ^; - EtOH + 1,

EtOH, 100), 170 (M ⁺ - 57.9), 166 (M ⁺ - 61)

71, 5), 154 (M ⁺ - +1 HCO2Et, 6), 153 (M ⁺ (M ⁺ - HC02Et - 1, 13), 142 (M ⁺ - 85, 15), 139 (M ⁺ - CH3 + HCO2Et 1, 8), 138 (M ⁺ - HCO 2 Et - CH ₃ , 65), 126 (M ⁺ - HCO 2 Et - CHO +2, 16), 125 (M ⁺ - HCO 2 Et - CHO +1, 34), 124 (M ⁺ HCO ² Et) - CHO, 51), 114 (M ⁺ - 113, 36), 111 (M ⁺ - HCO2Et - HNCHO + 1, 17), 110 (M ⁺ - HCO2Et - HNCHO, 36), 109 (M ⁺ HCO2Et - HNCHO - 1) , 20), 108 (M ⁺ - HCO ₂ Et - HNCHO - 2, 10), 98 (M ⁺ - 129, 6), 97 (M ⁺ - 130, 9), 96 (M ⁺ - 131, 12), 82 (M @ ⁺ - 145, 10), 68 (M @ ⁺ - 159, 48), 55 (M @ ⁺ - 172, 12).

Elementary analysis:

calculated: C = 63.41 H = 9.31 N = 6.16 found: C = 63.51 H = 9.02 N = 6.15

G) (E) -2-Formylamino-3-methyloct-2-enoic acid ethyl ester ((E (-34))

GC: R _t = 13.71 min (CP-Sil 8, 80-10-300) mp: 53 ° C (colorless, amorphous)

DC: Rf = 0.20 (ether: pentane - 4: 1)

R _f = 0.26 (DCM: ether - 4: 1)

The ratio of rotamers around the N-CHO bond is 65:35.

¹ H-NMR spectrum (400 MHz, CDCl ₃ ): δ = 8.16, 7.96 (dd, J = 1.64, 11.68, 0.65, 0.35 H, HC = O), 6.92, 6.83 (br s, br d.

··· · 4 · ·

J = 11.68, 0.65, 0.35 Η, HN), 4.23 (dq, J = 0.82, 7.14, 2H, OCH ₂ ), 2.56 (dtr, J = 7, 96, 18.13, 2H, C = CCH _2), 1.90 (dd,

J = 0.55, 39.55, 3H, C = CCH _3), 1.51 (m, 2H, CCH ₂ CH _2), 1.32 (dquin, J = 2.48, 7.14, 4H, CH ₃ CH ₂ CH ₂ ), 1.32 (m, 3H,

OCH ₂ CH ₃ ), 0.90 (dtr, J = 3.57, 7.14, 3H, CH ₂ CH ₃ ) ppm. l ^ C-NMR spectrum (100 MHz, CDC1 _3):

= 164.75, 164.14 (OC = O), 158.96 (HC = O), 151.38, 150.12 (C = CNH), 120.74, 119.48 (C = CCH ₃ ), 61.10, 60.90 (OCH ₂ ), 35.59 (CH ₂ ), 31.90 (CH ₂ ), 28.09, 28.04 (CH ₂ ), 22.48 (CH ₂ ), 20, 89 (C = CCH ₃ ), 14.17 (OCH ₂ CH ₃ ), 13.99 (CH ₂ CH ₃ ) ppm.

IR spectrum (KBr):

V - 3276 (vs) 2985 2962 (w), 2928 m 2859 m 2852 (v). 1717 (vs, C = O) , 1681 (s, OC = O) 1658 (vs , OC = O) 1508 (s), 1461 (s), 1395 (s), 1368 (vv) 1301 (vs) , 1270 (w ) 1238 (m), 1214 (s), 1185 m 1127 (m) 1095 (s), 1046 (ra), 1027 (w), 932 (m), 886 (s), 793 (m) , 725 (br s), 645 ( m),

607 (m), 463 (w) [cm ^-1 ].

MS (EI, 70eV):

M / z [%] = 227 (M ^& lt ^{; +} &^gt;, 19), 182 (M ^& lt ^{; +} & gt ^; - EtOH +1, 20), 181 (M &lt; ⁺ & gt ^; - 61.8), 156 (M ⁺ 71.7), 154 (M ⁺ - HCO2Et +1.6), 153 (M ⁺ - HCO2Et, 14), 152 (M ⁺ - HCO2Et - 1.12), 142 (M ⁺ - 85, 151), 139 (M ⁺ - HCO ₂ Et CH ₃ +1, 8), 138 (M ⁺ - HCO 2 Et - CH 3, 58), 126 (M ⁺ - HCO 2 Et CHO +2, 13), 125 ( M ⁺ - HCO 2 Et - CHO +1, 32), 124 (M ⁺ HCO ² Et - CHO, 46), 114 (M ⁺ - 113, 31), 111 (M ⁺ - HCO 2 Et hNCHO + 1, 16), 110 (M ^{+ -} - HCO 2 Et - HNCHO, 34), 109 (M ⁺ HCO ² Et - HNCHO - 1, 18), 108 (M ⁺ - HCO 2 Et - HNCHO - 2, 9), (M ⁺ - 129, 5), 97 (M ⁺ - 130) , 7), 96 (M ⁺ - 131, 11), 93 (M ⁺ - 134, 7), 82 (M ⁺ - 145, 9), 69 (M ⁺ - 158, 6), 68 (M ⁺ 159, 43), 55 (M ⁺ -172, 10).

• · * «« »» »»

Elemental Analysis: Calculated: C = 63.41 Found: C = 63.23

H) 3-Benzylsulfanyl-2-formylamino-3-methyl-octanoic acid ethyl ester (32)

H = 9.31 H = 9.38

N = 6.16 N = 6.10

Yield: 1.51 g (43 mmol, 98% of theory)

TLC: R _f = 0.51 (DCM: ether - 6: 1)

According to AAV 5, 0.28 ml (0.44 mmol) of n-butyllithium is reacted,

5.5 g (44 mmol) of benzyl mercaptan 35 and 1 g (4.4 mmol) of ethyl (E) - and (Z) -2-formylamino-3-methyl-oct-2-enoic acid 34 in 40 ml of absolute THF (-78) ° C to RT). The resulting colorless oil was purified by column chromatography with DCM / ether (6: 1) to give a colorless, viscous oil.

The resulting diastereomers may be separated from each other by preparative HPLC or by crystallization in pentane / ethanol (10: 1).

J) Threo-diastereomer ((threo) -32):

t ··· • »

Mp: 75 ° C de:> 96% ( ¹³ C-NMR)

HPLC ´19.38 min (ether: pentane = 85:15) prep

The ratio of rotamers around the N-CHO bond is 91: 9.

¹H-NMR spectrum (400 MHz, CDC1 _3):

δ = 8.22, 7.98 (s, d, J = 11.54, 0.91, 0.09 H, HC = O), 7.21 7.32 (kB, 5H, CH _ar ), 6 52, 6.38 (dm, J = 8.66, 0.91, 0.09 H, HN), 4.74 (d, J = 8.66, 1H, CHNH), 4.24 (ddq, J = 17.85, 10.71, 7.14, 2H, OCH ₂ ), 3.71 (s, 2H, SCH ₂ ), 1.59 (m, 3H, SCCH 3), 1.45 (dquin, 1 , 25, 7.97, 2H, CCH ₂ CH ₂ ), 1.20-1.45 (kB, 11H, CH ₃ CH ₂ CH ₂ CH ₂ CH ₂ + OCH ₂ CH ₃ ), 0.89 (dtr, J = 3.3, 7.00, 3H, CH ₂ CH ₃ ) ppm.

l ^ C-NMR spectrum (100 MHz, CDC1 _3):

= 170.37 (OC = 0), 160.90 (HC = O), 137.31 (C _{Ar qU} artJ '129.31 (HC _Ar ), 128.81 (HC _Ar ), 127.41 (HC _{Ar) para} ), 61.94 (OCH ₂ ), 57.00 (CHNH), 52.30 (CS), 38.59 (CH ₂ ), 33.31 (CH ₂ ), 32.42 (CH ₂ ), 24 .00 (CH ₂ ), 22.92 (CH ₂ ), 22.51 (SCCH ₃ ), 14.54 (OCH ₂ CH ₃ ), 14.42 (CH ₂ CH ₃ ) ppm.

IR spectrum (KBr):

= _V 3448 (m), 3184 (br vs), 3031 (m), 2975 (m), 2929 (s), 2899 (w), 2862 (m), 1954 (w), 1734 (vs, C = O ), 1684 (vs, OC = O), 1601 (s), 1561 (m), 1495 (m), 1468 (s), 1455 (m),

1296 (s), (vw) (m), (vw), 1441 (s), 1381 (s), 1330 (s), 1294 (m), 1195 (vs), 1158 (w), 1126 (s) 1096 (s), 1070

1028 (m), 1008 (m), 958 (m), 919 (m), 854 (m) 783 (m), 715 (m), 626 (m), 626 (m), 567 (m)

1248 (w), 1043,833,483 (s)

MS (EI, 70eV):

M / z [%] = 351 (M ^& lt ^{; +} &^gt;, 1), 324 (M + - C ₂ H ₅ , 1), 306 (M ^& lt ^{; +} & gt ^;) - C ₂ H ₅ OH - 1, 1), 278 (M ⁺ - 73) 1), 250 (M ⁺ - Et ₂ HC0 - HCO, 1), 223 (M ⁺ - 128 5), 222 (M ^& lt ^{; +} & gt ^;) 129, 16), 221 (M ^& lt ^{; +} & gt ^;) - EtO ₂ CCHNHCHO 100) , 184 (M ⁺ - 167.6) , 91 (M @ ⁺ - 260, 71).

Elementary calculated: found:

analysis:

C = 64.92 C = 64.88

H = 8.32 H = 8.40

N = 3.98 N = 3.92

(K) Erythro-diastereomer ((erythro) - 32):

Clear oil o: 82% ( ¹³ C-NMR)

HPLC: 20.61 min (ether: pentane = 85:15) prep

The ratio of rotamers around the N-CHO bond is 85: 15.

@ ¹ H-NMR (400 MHz, CDCl3): .delta.

S = 8.22, 7.97 (s, d, J = 11.54, 0.91, 0.09 H, HC = O), 7.20 7.34 (kB, 5H, CH _ar ), 6 61, 6.43 (br dm, J = 9.34, 0.91, 0.09%)

Δ, HN), 4.74 (d, J = 9.34, 1H, CHNH), 4.24 (ddq, J = 17.85, 10.71, 7.14, 2H, OCH ₂ ), 3, 77 (d, J = 11.53, IH, SCHH), 3.69 (d, J = 11.53, IH, SCHH), 1.70 (m, 2H, _CH2), 1.52 (m, 2H, CH ₂ ), 1.17-1.40 (kB, 10H, CH ₃ C + 2 x CH ₂ + OCH ₂ CH ₃ ), 0.90 (tr, J = 7.14, 3H, CH ₂ CH ₃ ) ppm.

l ^ C-NMR spectrum (100 MHz, CDC1 _3):

S = 169.87 (OC = O), 160.49 (HC = O), 137.05 (C _{Ar quart} ,), 128.91 (HC _Ar ), 128.40 (HC _Ar ), 126.99 ( HC _Ar , _para ) - 61.52 (OCH ₂ ), 56.81 (CHNH), 51.91 (CS), 37.51 (CH ₂ ), 32.83 (CH ₂ ), 32.13 (CH ₂₎ ), 23.65 (CH ₂ ), 23.19 (CH ₂ ), 22.55 (SCCH ₃ ), 14.11 (OCH ₂ CH ₃ ), 14.03 (CH ₂ CH ₃ ) ppm.

IR spectrum (capillary):

= _y 3303 (br vs), 3085 (br), 3062 (br), 3062 (br), 3029 (br), 2956 (br), 2935 (br), 2870 (br), 2748 (br) (br w), 1739 (vs, C = O), 1681 (vs, OC = O), 1603 (m vs), 1585 (vw), 1496 (vs), 1455 (vs), 1381 (vs), 1333 (b), 1197 (b vs), 1128 (b), 1095 (m), 1070 (b), 1030 (b), 971 (b), 918 (m), 859 (b), 805 (vw) 778 (ra), 714 (vs), 699 (vw), 621 (w), 569 (w), 484 (s) [cm ^-1 ].

MS (EI, 70eV):

M / z [%] = 351 (M ⁺ 1), 324 (M ⁺ - C2H5, 1), 306 (M ⁺ - C 2 H ₅ OH

- 1, 1), 278 (M ⁺ - 73) 1), 250 (M ^& lt ^{; +} & gt ^;) - HCO ₂ Et HCO, 1), 223 (M ⁺ - 128.6), 222 (M ⁺ - 129, 17) 222 (M ⁺ - EtO ₂ CCHNHCHO, 100), 184 (M ⁺ - 167.6) .91 (M ⁺ -) 260, 70). Elementary analysis: calculated: C = 64.92 H = 8.32 N = 3.98 found: C = 64.50 H = 8.12 N = 4.24

• · · ·

* «

L) 3-Ethylsulfanyl-2-formylamino-3-methyl-octanoic acid ethyl ester (33)

According to AAV 5, 0.28 ml (0.44 mmol) of n-butyllithium, 2.73 g (44 mmol) of ethyl mercaptan 36 and 1 g (4.4 mmol) of ethyl (E) -2-formylamino-3-methyl ester were reacted. -oct-2-ene (E) -34 in 40 mL absolute THF (-78 ° C to RT). The colorless oil obtained is purified by column chromatography with DCM / ether (6: 1). The product is obtained as a colorless, viscous oil,

Yield: 1.05 g (36.3 mmol, 82% of theory) de; 14% (according to ² Η- and ¹³ C-NMR)

TLC: R _f = 0.49 (DCM; ether = 4: 1)

The ratio of rotamers around the N-CHO bond is 91 H-NMR (400 MHz, CDCl3):

S = 8.26 (s, 0.91 H, HC = 0), 8.02 (d, J = 11.82 + d, J = 11.81, 0.09 H, HC = 0), 6, 79 (d, J = 9.34 + d, J = 8.71, 0.91 Η, HN), 6.55 (m, 0.09 Η, HN), 4.77 (d, J = 9, 34, 0.57 H, CHNH), 4.64 (d, J = 8.71, 0.43 H, CHNH), 4.22 (m, 2H,

OCH ₂ ), 2.50 (m, 2H, SCH ₂ ), 1.43-1.73 (kB, 4H, 2 x CH ₂ ), 1.20-1.37 (kB, 10H), 1.18 (tr, J = 7.42 + tr, J = 7.00, 3H, SCH ₂ CH ₃ ), 0.90 (dtr, J = 4.71, 7.14, 3H, CH ₂ CH ₃ ) ppm.

· A a a a a a a a a a a a a a a a a a f f f f f f f f f f @ 1 H-NMR spectrum (100 MHz, CDCl3): .delta.

δ = 170.36, 170.25 (0C = 0), 160.98, 160.93 (HC = O), 61.74, 61.70 (OCH ₂ ), 57.15, 57.02 (CHNH) , 51.19 (SC _Quarx), 38.66, 37.86 _(CH2), 32.51, 32.42 _(CH2), 23.94 _(CH2), 23.45, 22.50 (SCCHs ₃ ), 22.90, 22.85 (CH ₂ ), 22.17, 22.11 (CH ₂ ), 14.44,

14.41 (OCH ₂ CH ₃ ), 14.38, 14.36 (SCH ₂ CH ₃ ), 14.27, 14.25 CH ₂ CH ₃ ) ppm.

IR spectrum (capillary):

_v = 3310 (bs), 2959 (bs), 2933 (bs), 2871 (bs), 2929 (bs), 2746 (bs), 1739 (bs, C = O), 1670 (bs, OC = O) ), 1513 (m), 1460 (m), 1468 (m), 1381 (s), 1333 (m), 1298 (vv) m), 1096 (m), 1070 (w), 1030 (s), 978 (w), 860 (m), 833 (m), 727 (wm) [cm ^-1 ].

MS (EI, 70eV):

M / z [%] = 289 (M ⁺ 1), 260 (M ⁺ - C2Hg, 1), 244 (M ⁺ - C 2 H ₅ OH - 1, 1), 228 (M ⁺ - SC2H5, 1), 188 (M ⁺ - HCO 2 Et-HCO, 1), 161 (M ⁺ - 128, 5), 160 (M ⁺ - 129, 11), 159 (M ⁺ - EtO ₂ CCHNHCHO, 100), 97 (M ⁺ - 192, 11), 89 (M ⁺ - 200, 11), 75 (M ⁺ - 214)

5), 55 (M ⁺ - 214, 14),

Elementary analysis:

calculated: C = 58.10 H = 9.40 N = 4.84 found: C = 57.97 H = 9.74 N = 5.13

Crystallization in pentane / ethanol gave high purity threo-diastereomer (threo) -33 crystals after 30 days.

M)

Threo-diastereomer (threo) -33 • · ·

de ·. 86% (according to ⁴³ C-NMR)

Tt: 45.5 ° C (colorless, crystalline) ⁴ H-NMR spectrum (300 MHz, CDCl 3):

δ = 8.26, 8.01 (br s, dd, J = 11.81 H, 0.91, 0.09 H, HC = 0), 6.61, 6.40 (dm, J = 9, 06, 0.91, 0.09 H, HN), 4.77 (d, J = 9.34, 0.57 H, CHNH), 4.22 (ddq, J = 7.14, 10.72, 17.79, 2H, OCH ₂ ), 2.50 (ddq, J = 7.42, 10.72, 27.36, 2H, SCH ₂ ), 1.42 1.76 (kB, 4H, 2 x CH ₂ ), 1.24-1.38 (KB, 10H), 1.18 (dtr,

J = 3.3, 7.42, 3H, SCH ₂ CH ₃ ), 0.90 (tr, J = 7.14, 3H, CH ₂ CH ₃ ) ppm.

⁴³ C-NMR (75 MHz, CDC1 _3):

δ = 170.13 (OC = O), 160.71 (HC-O), 61.50 (OCH ₂ ), 56.85 (CHNH), 50.97 (SC _quart ), 37.64 (CH ₂ ) , 32.22 (CH ₂ ), 23.66 (CH ₂ ), 23.47 (SCCH ₃ ), 22.60 (CH ₂ ), 21.81 (CH ₂ ), 14.09 (OCH ₂ CH ₃ ) , 14.07 (SCH ₂ CH ₃ ), 13.93 (CH ₂ CH ₃ ) ppm.

IR spectrum (KBr):

= _y 3455 (m), 3289 (s), 3036 (w), 2981 (s), 2933 (vs),

2860 2829 (s) 2755 (br, m), 2398 (vv) 2344 (vw), 2236 (vw), 2062 (w) 1737 (vs, C = 0) 1662 (vs , OC = 0), 1535 (with), 1450 m, 1385 m s), 1373 (s), 1334 (vs) 1267 (m), 1201 (vs) 1154 (m), 1132 (s), 1118 (v), 1065 m 1050 (w), 1028 (s), 1016 (m), 978 (m) ), 959 (w), 929 (w), 896 (m) , 881 m 839 (w), 806 (m), 791 (m) , 724 (s), 660 (m) 565 ( m) [cm ⁴ ].

• · *

MS (CI, isobutane):

M / z [%] = 346 (M ⁺⁺ 1, 2), 292 (M ⁺ +3, 6), 291 (M ⁺ +2, 17), 290 (M ⁺ , 1, 100), 245 (M ⁺ - C ₂ H ₈ OH, 1), 228 (M ⁺ - SC ₂ H ₅ , 6), 159 (M ⁺ - EtCl 4 CCHNHCHO, δ).

Elementary analysis:

calculated: C = 58.10 H = 9.40 N = 4.84 found: C = 58.05 H = 9.73 N = 4.76

The diastereomer (ervthro) -33 has so far been obtained by crystallization (tbreo) -33 with only a de 50% value, no separate analysis has been performed.

List of abbreviations

AAV General working rules abs. absolute eq. equivalent AcCl acetic acid chloride Ar aromat off calculated Bn benzyl Br ine saturated NaCl solution BuLi buty11i thium DC thin chromatography DIPA diisopropylamine DCM dichloromethane de excess diastereomer DMSO dimethylsulfoxide dr ratio of diastereomers ee excess enantiomer Et ethyl et al. et al.

• ·

GC gef. ges. HPLC IR Cons. Pour.

Me min

MS

NMR quart.

Ex

R

RT

Sdp.

Smp.

TBS

Tf

THF

TMS

TsOH

In gas chromatography found saturated high pressure liquid chromatography infrared concentrated lithium methyl minute

Mass spectroscopy

Nuclear magnetic resonance quaternary propyl organic residue room temperature boiling point melting point tert-butyldimethylsilyl Triflat tetrahydrofuran trimethylsilyl toluenesulfonic acid volume

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119, 12974.

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Claims (17)

A process for producing a compound of formula 31 wherein: R 1, R 2 and R 3 are independently selected from C 1 -C 10 alkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted; and * indicates a stereoselective center R 4 is selected from alkyl of 1 to 10 carbon atoms, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; saturated or unsaturated, mono- or polysubstituted or unsubstituted cycloalkyl of 3 to 8 carbon atoms; or aryl, C 3 -C 8 cycloalkyl or heteroaryl bonded via saturated or unsaturated C 1 -C 3 alkyl, in each case unsubstituted or mono- or multiply substituted; wherein the compound of formula 30 reacts under Michael addition conditions with a compound of formula R4SH according to the following reaction scheme: Reaction I wherein the compounds of formula R4SH are used as lithium thiolates or in reaction or prior to reaction I react to lithium thiolates and / or chiral catalysts selected from: auxiliary chiral reagents, in particular diether (S, S) -1,2-dimethoxy-1, 2-dienylethane; Lewis acids and / or Bronsted bases or combinations thereof are used and optionally subsequently hydrolyzed with bases, in particular sodium hydroxide, and optionally purified, preferably by column chromatography. Process according to claim 1, characterized in that the compounds of the formula R 4 SH are used as lithium thiolates or reacted with lithium thilates in or before reaction I. 3. Process according to either of Claims 1 and 2, characterized in that butyllithium (BuLi) is used prior to reaction I to react the compounds of formula R4SH to lithium thiolates, preferably in an equivalent ratio of BuLi: R RSH between 1: 5 and 1:20, especially 1: 10 and reacted with R ₄ SH and / or the reaction is carried out at temperatures £ 0 ° C and / or in an organic solvent, especially toluene, ether, THF or DCM, especially in THF. Process according to one of Claims 1 to 3, characterized in that at the start of reaction I the reaction temperature is at 0 ° C, preferably between -70 ^° C and -80 ° C, especially at -78 ° C and during reaction I the temperature is brought to room temperature or at the start of reaction I the reaction temperature = £0 ° C, preferably lies between -30 ° C and -20 ° C, especially at -25 ° C and during reaction I, the temperature is brought to a temperature between -20 ° C and -10 ° C, in particular -15 ° C. Process according to one of Claims 1 to 4, characterized in that the reaction I is carried out in an organic solvent, preferably in toluene, ether, THF or DCM, in particular in THF or in a non-polar solvent, in particular in DCM or toluene. . Process according to one of Claims 1 to 5, characterized in that the diastereomers are separated after reaction I, preferably by preparative HPLC or crystallization, in particular using a pentane / ethanol (10: 1) solvent and with cooling. Process according to any one of claims 1 to 6, characterized in that the separation of the enantiomers is carried out before the separation of the diastereomers. 8. Process according to any one of claims 1 to 7, characterized in that R ¹ represents alkyl of 1 to 6 carbon atoms, saturated or unsaturated, branched or unbranched, mono- or multiply substituted or unsubstituted, and R represents alkyl of 2 to 9 carbon atoms, saturated or unsaturated, branched or unbranched, once or multiply substituted or unsubstituted, preferably is R @ 1 represents alkyl of 1 to 2 carbon atoms, mono- or multiply substituted or unsubstituted, in particular methyl or ethyl, and R @ 1 represents alkyl of 2 to 9 carbon atoms, preferably alkyl of 2 to 7 carbon atoms, saturated or unsaturated, branched or unbranched , singly or multiply substituted or unsubstituted, in particular ethyl, propyl, n-propyl, i-propyl, butyl, n-butyl, i-butyl, tert-butyl, pentyl, hexyl or heptyl, in particular τ 9 R is methyl and R is n-butyl. The method of any one of claims 1 to 8, and characterized in that R is selected from alkyl of 1 to 3 carbon atoms, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; preferably methyl or ethyl. Process according to any one of claims 1 to 9, characterized in that it is selected from alkyls having 1 to 6 carbon atoms, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; phenyl or thiophenyl, unsubstituted or monosubstituted, preferably OCH ^ CH ^ OH, SH, CF _3, F, Cl, Br or I substituted; or via saturated CH ₃ - bonded phenyl, unsubstituted or monosubstituted, preferably 0CH _3, CH _3, OH, SH, CF _3, F, Cl, Br or I-substituted; • 4 · 4 4 4 4 4 4 4 44 44 preferably is R ⁴ is selected from alkyl of 1 to 6 carbon atoms, saturated, unbranched and unsubstituted, especially methyl, ethyl, propyl, n-propyl, i-propyl, butyl, n-butyl, i-butyl, tert-butyl, pentyl or hexyl; phenyl or thiophenyl, unsubstituted or mono- (preferably OCH3, CH3, OH, SH, CF3, F, Cl, Br or I) substituted; or via saturated CH3-linked phenyl, unsubstituted or once (preferably OCH3), CH 3, OH, SH, CF 3, F, Cl, Br or I) substituted, especially with R ^{4 is} selected from methyl, ethyl or benzyl, unsubstituted or mono- (preferably OCH 2, CH 2, OH, SH, CF 3, F, Cl, Br or I) substituted. The method according to any one of claims 1 to 10, characterized in that the thiolate is used stoichiometrically, TMSCl is used and / or the chiral proton donor R ⁺ -H is then used, or that compound 30 is modified sterically demanding prior to reaction I ( a large group, preferably TBDMS, A process according to any one of claims 1 to 11, wherein the compound of formula 31 is 3-ethylsulfanyl-2-formylamino-3-methyloctanoic acid ethyl ester or ethyl ester 3-Benzylsulfanyl-2-formylamino-3-methyloctanoic acid, the compound of formula 30 is ethyl 2-formylamino-3-methyloct-2-enoic acid ethyl ester, and R 15 SH is ethylmercaptan or benzylmercaptan. 13. A compound of formula 31 wherein 19 9 R, R and independently of one another are selected from alkyls having from 1 to 10 carbon atoms, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; * indicates a stereoselective center, and R ⁴ is selected from alkyl of 1 to 10 carbon atoms, saturated or unsaturated, branched or unbranched, mono- or multiply substituted or unsubstituted; saturated or unsaturated, unsubstituted or singly or multiply substituted cycloalkyl having from 3 to 8 carbon atoms; aryl or heteroaryl, in each case unsubstituted or monosubstituted; or aryl, C 3 -C 8 cycloalkyl or heteroaryl bonded via saturated C 1 -C 3 alkyl, in each case unsubstituted or mono- or multiply substituted; in the form of their racemates, enantiomers, diastereomers, in particular mixtures of their enantiomers or diastereomers or individual enantiomers or diastereomers; or in the form of their physiologically tolerable acidic v · · φ v V V V V V V V V V V V V V V V V V V V V And basic salts or salts with cations or bases or with anions or acids or in the form of free acids or bases. 14. A compound according to claim 13, wherein F5 is alkyl of 1 to 6 carbon atoms, saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted, and R is alkyl of 2 to 9 carbon atoms, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted, preferably r? represents alkyl having 1 to 2 carbon atoms, mono- or polysubstituted or unsubstituted, in particular methyl or ethyl, and R is alkyl of 2 to 9 carbon atoms, preferably alkyl of 2 to 7 carbon atoms, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted, especially ethyl, propyl, n-propyl, i-propyl, butyl, n-butyl, i-butyl, tert-butyl, pentyl, hexyl or heptyl, in particular Ί 9 R is methyl and R is n-butyl. Compound according to either of Claims 13 or 14, characterized in that R is selected from alkyls having 1 to 3 carbon atoms, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted, preferably methyl or ethyl. Compound according to one of Claims 13 to 15, characterized in that R is selected from α 9 · 9 9 9 9 9 9 9 9 * 9 9 999 9 9 · ··· * «· · · · ft« 9-, keels of 1 to 6 carbon atoms, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; phenyl or thiophenyl, unsubstituted or monosubstituted (preferably with OCH ^ CH ^ OH, SH, CF _3, F, Cl, Br or I); or via saturated CH 2 - bonded phenyl, unsubstituted or mono- (preferably OCH 2, CH 3, OH, SH, CF 3, F, Cl, Br or I) substituted; preferably R ⁴ is selected from alkyl of 1-6 carbon atoms, saturated, unbranched and unsubstituted, in particular methyl, ethyl, propyl, n-propyl, i-propyl, butyl, n-butyl, i-butyl, tert. butyl, pentyl or hexyl; phenyl or thiophenyl, unsubstituted or monosubstituted (preferably with OCH-CH _3, OH, SH, CF ^, F, Cl, Br or I); or via saturated CH ^ - bonded phenyl, unsubstituted or singly (preferably _{OCH3, CH3,} OH, SH, CF _3, F, Cl, Br or I) substituted. R ⁴ is particularly selected from methyl, ethyl or benzyl, unsubstituted or monosubstituted (preferably with _{OCH3, CH3,} OH, SH, CFj, F, Cl, Br or I), A compound according to any one of claims 13 to 16, wherein the compound is selected from 3-ethylsulfanyl-2-formylamino-3 methyloctanoic acid ethyl esters or 3-benzylsulfanyl-2-formylamino-3-methyloctanoic acid ethyl esters.